CENTRALLY ACTIVE AND ORALLY BIOAVAILABLE ANTIDOTES FOR ORGANOPHOSPHATE EXPOSURE AND METHODS FOR MAKING AND USING THEM (Fri, 22 Aug 2014)
In alternative embodiments, the invention provides nucleophilic hydroxyimino- acetamido alkylamine antidotes that cross the blood-brain barrier (BBB) to catalyze the hydrolysis of organophosphate (OP)-inhibited human acetylcholinesterase (hAChE) in the central nerve system (CNS). The hydroxyimino-acetamido alkylamines of the invention are designed to fit within AChE active center gorge dimensions, bind with reasonable affinity, and react with the conjugated phosphate atom in the gorge. The hydroxyimino- acetamido alkylamines of the invention are also designed to possess ionization states that govern affinity and reactivity for the two linked hAChE re-activation steps. In alternative embodiments, the invention provides pumps, devices, subcutaneous infusion devices, continuous subcutaneous infusion devices, infusion pens, needles, reservoirs, ampoules, a vial, a syringe, a cartridge, a disposable pen or jet injector, a prefilled pen or a syringe or a cartridge, a cartridge or a disposable pen or jet injector, a two chambered or multi- chambered pump, a syringe, a cartridge or a pen or a jet injector, comprising a compound of the invention.
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Production of Carrier-Peptide Conjugates Using Chemically Reactive Unnatural Amino Acids (Fri, 20 Jun 2014)
<p id="p-0001" num="0000">Provided are methods of making carrier polypeptide that include incorporating a first unnatural amino acid into a carrier polypeptide variant, incorporating a second unnatural amino acid into a target polypeptide variant, and reacting the first and second unnatural amino acids to produce the conjugate. Conjugates produced using the provided methods are also provided. In addition, orthogonal translation systems in methylotrophic yeast and methods of using these systems to produce carrier and target polypeptide variants comprising unnatural amino acids are provided.</p>
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TARGETED COVALENT PROBES AND INHIBITORS OF PROTEINS CONTAINING REDOX-SENSITIVE CYSTEINES (Fri, 13 Jun 2014)
Covalent, irreversible small-molecule inhibitors that modify the sulfenyl form (i.e., sulfenic acid, RSOH and sulfenamide, RSNR'2) of therapeutically important proteins (particularly kinases and phosphatases) are disclosed, where the compositions include a compound having a substituted aryl or heterocyclic core structure that promotes binding interactions with a specific protein, and a nucleophilic reaction center (carbon, nitrogen, sulfur, or phosphorous) that is capable of forming a covalent bond with a sulfenic acid- or sulfenamide-modified cysteine residue in the protein. Methods for synthesizing these compounds are also disclosed, as well as methods of using them for determining the bioactivity of a chemical composition comprising an active compound toward a specific protein and for determining the potency of an inhibitor against a specific protein.
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POLYMERIZATION METHOD AND POLYMERS FORMED THEREWITH (Fri, 13 Jun 2014)
Condensation of fluoro-substituted and silyl-substituted monomers provides polymers suitable for use, e.g., as engineering polymers. A monomer composition is condensed in the presence of a basic catalyst. The monomer composition contains a compound of formula F-X-F and a compound of formula (R1)3Si-Z-Si(R1)3, and forms an alternating X-Z polymer chain and a silyl fluoride byproduct. X has the formula -A(-R2-A)n -; each A is SO2, C(=O), or Het; R2 is an organic moiety; n is 0 or 1; Het is an aromatic nitrogen heterocycle; Z has the formula -L-R3-L-; each L is O, S, or N(R4); and each R3 is an organic moiety, and R4 comprises H or an organic moiety.
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C20'-UREA DERIVATIVES OF VINCA ALKALOIDS (Fri, 13 Jun 2014)
A vinca alkaloid compound that is substituted at the 20'-position with a urea or thiourea group is disclosed. The urea's proximal nitrogen atom bonded to the 20'-position carbon atom is secondary, whereas the distal nitrogen atom can be unsubstituted only when the compound contains an optionally present 10'-fluoro substituent, and is otherwise preferably mono- or di-substituted. Methods of preparing the compounds are disclosed as are compositions for their use and methods of treatment using a compound.
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SMALL MOLECULE LXR INVERSE AGONISTS (Fri, 06 Jun 2014)
The invention is directed to small molecule inverse agonists of the liver X receptor, LXR. These compounds have potential use in the treatment of the following disorders: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, obesity, insulin resistance, and metabolic syndrome. The invention is directed, in various embodiments, to small molecule inverse agonists of the liver X receptor, LXR. Administration of an effective amount of a compound of the invention, such as compound of formula (I), can be used to suppress hepatic lipogenesis, inflammation, or hepatic lipid accumulation in a mammal.
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HUMAN AMINOACYL-tRNA SYNTHETASE POLYPEPTIDES USEFUL FOR THE REGULATION OF ANGIOGENESIS (Fri, 09 May 2014)
<p id="p-0001" num="0000">Methods of enhancing angiogenesis utilizing carboxy-terminal truncated human tyrosyl-tRNA synthetase (TyrRS) are disclosed. The truncated human TyrRS polypeptides comprise residues 1-364 or residues 1-343 of full length human TyrRS (SEQ ID NO: 2).</p>
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COMPOUNDS AND METHODS FOR INDUCING CHONDROGENESIS (Fri, 25 Apr 2014)
<p id="p-0001" num="0000">The present invention provides compounds and compositions for the amelioration of arthritis and joint injuries by inducing mesenchymal stem cells into chondrocytes.</p>
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COMPOUNDS THAT EXPAND HEMATOPOIETIC STEM CELLS (Fri, 25 Apr 2014)
<p id="p-0001" num="0000">The present invention relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. The invention further relates to a cell population comprising expanded hematopoietic stem cells (HSCs) and its use in autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficient and autoimmune diseases and diverse hematopoietic disorders to reconstitute the hematopoietic cell lineages and immune system defense.</p>
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Chemically Programmed Vaccination (Fri, 04 Apr 2014)
<p id="p-0001" num="0000">Provided herein is a method for chemically programmed vaccination. Methods include inducing a covalent-binding polyclonal antibody response in a subject and programming the polyclonal response with a targeting compound.</p>
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ULTRALONG COMPLEMENTARITY DETERMINING REGIONS AND USES THEREOF (Fri, 28 Mar 2014)
<p id="p-0001" num="0000">Disclosed herein are immunoglobulin constructs comprising at least one immunoglobulin domain or fragment thereof; and a therapeutic polypeptide or derivative or variant thereof attached to or inserted into said immunoglobulin domain. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a knob domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said knob domain of the CDR3H. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a stalk domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said stalk domain of the CDR3H. Also described herein are methods and compositions comprising the immunoglobulin constructs described herein for treatment and prevention of a disease or condition in a subject.</p>
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STRUCTURES OF HUMAN HISTIDYL-TRNA SYNTHETASE AND METHODS OF USE (Fri, 07 Mar 2014)
<p id="p-0001" num="0000">Provided are histidyl-tRNA synthetase variant polypeptides, X-ray crystallographic and NMR spectroscopy structures of HRS polypeptides, and related compositions and methods for therapy and drug discovery.</p>
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SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES (Fri, 07 Mar 2014)
The invention provides a series of bioactive small molecules that target expanded r(CGG) repeats, termed r(CGG)exp, that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5'CGG/3'GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Specifically, dimeric compounds incorporating two 9-hydroxyellipticine analog structures can even more potently bind the 5'CGG/3'GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG) repeats, such as r(CGG)exp. Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp-protein aggregates.
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ULTRALONG COMPLEMENTARITY DETERMINING REGIONS AND USES THEREOF (Fri, 21 Feb 2014)
<p id="p-0001" num="0000">Disclosed herein are immunoglobulin constructs comprising at least one immunoglobulin domain or fragment thereof; and a therapeutic polypeptide or derivative or variant thereof attached to or inserted into said immunoglobulin domain. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a knob domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said knob domain of the CDR3H. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a stalk domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said stalk domain of the CDR3H. Also described herein are methods and compositions comprising the immunoglobulin constructs described herein for treatment and prevention of a disease or condition in a subject.</p>
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TETRACYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 14 Feb 2014)
<p id="p-0001" num="0000">Certain tetracyclic compounds are described, which may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).</p>
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6"-AMINO-6"-DEOXYGALACTOSYLCERAMIDES (Fri, 07 Feb 2014)
<p id="p-0001" num="0000">This invention relates to galactosylceramide compounds.</p>
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KLF5 MODULATORS (Fri, 31 Jan 2014)
The invention provides potent inhibitors of small molecule inhibitors of Krüppel-like factor 5 (KLF5) expression. Compounds of the invention are small molecule inhibitors of KLF5 expression which can be effective delay or prevent colon cancer onset, halt growth of existing tumors, and/or decrease reoccurrence. The compounds can be effective vs. many tumor types whose progression is in part mediated by KLF5, including colorectal cancers. Lowering KLF5 levels with an inhibitor of this invention may also impact other disease states, including diabetes, obesity, lipid homeostasis, cardiovascular disease, and arthritis.
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PALLADIUM(II)-CATALYZED SELECTIVE FLUORINATION OF BENZOIC ACIDS AND DERIVATIVES (Fri, 17 Jan 2014)
<p id="p-0001" num="0000">A new method of ortho-fluorination for selectively fluorinating a benzoic acid or derivative compound where an aryl C—H bond is directly replaced by an aryl C—F bond is provided. The method comprises reacting a compound having the formula:</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="20.83mm" wi="55.12mm" file="US20140018566A1-20140116-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <ul id="ul0001" list-style="none"> <li id="ul0001-0001" num="0000"> <ul id="ul0002" list-style="none"> <li id="ul0002-0001" num="0000">wherein X is at least one substitution group attached with a benzene ring and Ar is an aromatic substitution group comprising at least one fluorine atom, <br/> and a mixture comprising a palladium (II) catalyst and a fluorinating reagent to form at least one of the ortho-fluorinated compounds having the formulae </li> </ul> </li> </ul> </p> <p id="p-0003" num="0000"><chemistry id="CHEM-US-00002" num="00002"> <img id="EMI-C00002" he="46.06mm" wi="58.34mm" file="US20140018566A1-20140116-C00002.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p> <p id="p-0004" num="0000">with good yield and selectivity.</p>
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NOVEL PHENYL GLYOXAL PROBES (Fri, 13 Dec 2013)
Novel phenyl-glyoxal based anti-citrulline probes and methods of synthesis are provided. Methods of use, such as, the development of methods for monitoring substrate citrullination over time; for identifying citrullinated proteins from cells are described.
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INHIBITORS OF FOCAL ADHESION KINASE (Fri, 25 Oct 2013)
<p id="p-0001" num="0000">The invention provides inhibitors of focal adhesion kinase, an enzyme involved in the attachment of the cytoskeleton of a cell to an extracellular matrix, which has been implicated in processes such as cell migration, cell proliferation, and cell survival. The inhibitors are derivatives of a 5-substituted 2,4-diaminopyridine wherein the substituents are as defined herein. The invention also provides a method of using the inhibitors in treatment of cancer, and methods of preparation of the inhibitors by use of coupling reactions.</p>
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ANTI-CANCER SERINE HYDROLASE INHIBITORY CARBAMATES (Fri, 25 Oct 2013)
<p id="p-0001" num="0000">Serine hydrolases are implicated in malconditions such as cancer, central nervous system disorders, cardiovascular disorders, obesity, and metabolic disorders. Many serine hydrolases expressed in proteomic libraries are of unknown function in vivo. Compounds identified through library versus library screening can be used for treatment of malconditions associated with the specific serine hydrolase KIAA1363 (also known as AADACL1). A library of inhibitors of KIAA1363 was prepared and candidate compounds were identified as a potent inhibitors having submicromolar IC<sub>50 </sub>values. An exemplary compound of the invention was shown to be an effective inhibitor of prostate cancer pathogenesis. Other inhibitory compounds of the invention comprising fluorophore groups are shown to be effective in spatial and temporal localization of the serine hydrolase in cells and tissues.</p>
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POLYPEPTIDES AND THEIR USE IN TREATING METAPNEUMOVIRUS (MPV) INFECTION (Fri, 11 Oct 2013)
Polypeptides and compositions thereof are provided for treating or limiting metapneumovinjs (MPV) infection, as well as methods for designing such polypeptides. In further aspects, methods of using said isolated polypeptides, VLPs or pharmaceutical compositions are provided, which include methods for treating a metapneumovirus (MPV) infection, methods for limiting development of an MPV infection, methods for generating an immune response in a subject, methods for monitoring an MPV-induced disease in a subject and/or monitoring response of the subject to immunization by an MPV vaccine, methods for detecting MPV binding antibodies, methods for producing MPV antibodies, and methods of preventing an MPV infection.
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ΑΖΑ-β-LACTAM COMPOUNDS AND METHODS OF USING (Fri, 11 Oct 2013)
The invention is directed to methods of modulation of serine hydrolase ABHD10, which can be selective with respect to other serine hydrolases such as PME-1. The compounds of the invention, or compounds useful in practice of a method of the invention, are aza-β-lactams, of which the (R)-enantiomer is preferred, for modulation of ABHD10. Methods of preparation are provided comprising the cycloaddition of dialkylazodicarboxylates with ketenes using the catalyst PPY*. The invention provides methods of treatment of conditions in patients for which modulation of ABHD10 is indicated, including pain, inflammation, metabolic disorders, solid tumors, or obesity.
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CYCLIC PRODRUGS OF DUOCARMYCIN ANALOGS (Fri, 04 Oct 2013)
The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spirocyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.
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CARBAMATE COMPOUNDS AND OF MAKING AND USING SAME (Fri, 27 Sep 2013)
Provided herein are carbamate compounds which may be useful in the treatment of, for example, pain, solid tumors and/or obesity.
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Orthogonal Translation Components for the in Vivo Incorporation of Unnatural Amino Acids (Fri, 20 Sep 2013)
<p id="p-0001" num="0000">The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetase that can incorporate unnatural amino acid into proteins produced in eubacterial host cells such as <i>E. coli</i>, or in a eukaryotic host such as a yeast cell. The invention provides, for example but not limited to, novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing unnatural amino acids, and translation systems.</p>
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Unnatural Reactive Amino Acid Genetic Code Additions (Fri, 20 Sep 2013)
<p id="p-0001" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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BROAD SPECTRUM ANTIBIOTIC ARYLOMYCIN ANALOGS (Fri, 20 Sep 2013)
Arylomycin analogs are provided, wherein the analogs can have broad spectrum bioactivity. Resistance to the antibiotic bioactivity of natural product arylomycin in a range of pathogenic bacterial species has been found to depend upon single amino acid mutations at defined positions of bacterial Signal Peptidases (SPases), wherein the presence of a proline residue confers arylomycin resistance. Arylomycin analogs are provided herein that can overcome that resistance and provide for a broader spectrum of antibiotic bioactivity than can natural product arylomycins such as arylomycin A2. Methods for determining if a bacterial strain is susceptible to narrow spectrum arylomycin antibiotics, or if a broad spectum analog is required for treatment, is provided. Pharmaceutical compositions and methods of treatment of bacterial infections, and methods of synthesis of arylomycin analogs, are provided.
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WEE1 DEGRADATION INHIBITORS (Sat, 07 Sep 2013)
The invention provides compounds that inhibit the degradation of Weel. The compounds of the present invention are generally N-((1H-benzo[d]imidazol-2- yl)methyl)-9H-purin-6-amines. Compounds of the invention can be used for treatment of malconditions in patients for which inhibition of Weel is medically indicated, for example cancer, Alzheimer's, neurological disorders, psychiatric disorders, or inflammation-related disorders.
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SUBSTITUTED PYRIMIDINYL-AMINES AS PROTEIN KINASE INHIBITORS (Fri, 06 Sep 2013)
<p id="p-0001" num="0000">The present invention provides novel substituted pyrimidinyl-amines that are useful as inhibitors of protein kinases, especially c-Jun N-terminal kinases (JNK) and pharmaceutical compositions thereof and methods of using the same for treating conditions responsive to the inhibition of the JNK pathway.</p>
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Compositions and Methods for Treatment of Neurodegenerative Disease (Fri, 23 Aug 2013)
<p id="p-0001" num="0000">Compounds, compositions, kits and methods for treating conditions related to neurodegeneration or ocular disease, are disclosed.</p>
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CRYSTALS OF MEMBRANE PROTEINS (Fri, 16 Aug 2013)
<p id="p-0001" num="0000">A polypeptide in crystalline form comprises a G-protein coupled receptor (GPCR) with an IC3 loop substituted by an amino acid residue sequence of lysozyme.</p>
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TREATMENT OF FRIEDREICH'S ATAXIA USING HISTONE DEACETYLASE INHIBITORS (Fri, 16 Aug 2013)
<p id="p-0001" num="0000">The invention provides methods of treating Friedreich's ataxia using histone deacetylase inhibitors.</p>
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COMPOSITIONS AND METHODS FOR INDUCING CELL DEDIFFERENTIATION (Fri, 02 Aug 2013)
<p id="p-0001" num="0000">The present invention provides compounds, compositions and methods for dedifferentiating lineage committed mammalian cells into stem cells. The present invention also provides methods of inducing dedifferentiation of lineage committed mammalian cells into stem cells, which can be further differentiated into various lineage committed cells. Methods of identifying additional compounds useful for inducing dedifferentiation of lineage committed cells into stem cells are also provided.</p>
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ULTRALONG COMPLEMENTARITY DETERMINING REGIONS AND USES THEREOF (Fri, 19 Jul 2013)
Disclosed herein are immunoglobulin constructs comprising at least one immunoglobulin domain or fragment thereof; and a therapeutic polypeptide or derivative or variant thereof attached to or inserted into said immunoglobulin domain. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a knob domain in the complementarity- determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said knob domain of the CDR3H. Also provided are immunoglobulin constructs comprising a mammalian immunoglobulin heavy chain comprising at least a portion of a stalk domain in the complementarity-determining region 3 (CDR3H) or fragment thereof; and a therapeutic polypeptide attached to or inserted into said stalk domain of the CDR3H. Also described herein are methods and compositions comprising the immunoglobulin constructs described herein for treatment and prevention of a disease or condition in a subject.
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HUMANIZED ANTIBODIES WITH ULTRALONG CDR3S (Fri, 19 Jul 2013)
The present disclosure provides humanized antibodies, including antibodies comprising an ultralong CDR3 (e.g. bovine) and uses thereof.
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CARBAMATE COMPOUNDS AND OF MAKING AND USING SAME (Fri, 12 Jul 2013)
This disclosure provides compounds and compositions which may be modulators of MAGL and/or ABHD6 and their use as medicinal agents, processes for their preparation, and pharmaceutical compositions that include disclosed compunds as at least one active agent. The disclosure also provides for method of treating a patient in need thereof, where the patient is suffering from indications such as pain, solid tumor cancer and/or obesity comprising administering a disclosed compound or composition.
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TARGETING COMPOUNDS (Fri, 05 Jul 2013)
<p id="p-0001" num="0000">The present invention provides antibody targeting compounds in which the specificity of the antibody has been reprogrammed by covalently or noncovalently linking a targeting agent to the combining site of an antibody. By this approach, the covalently modified antibody takes on the binding specificity of the targeting agent. The compound may have biological activity provided by the targeting agent or by a separate biological agent. Various uses of the invention compounds are provided.</p>
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Enzyme Regulating Ether Lipid Signaling Pathways (Fri, 28 Jun 2013)
<p id="p-0001" num="0000">A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.</p>
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HEROIN HAPTENS, IMMUNOCONJUGATES AND RELATED USES (Fri, 28 Jun 2013)
The present invention provides novel heroin hapten compounds and heroin immunoconjugates which can be used for in vivo production of antibodies that specifically bind to heroin and its psychoactive metabolites. The invention also provides methods of using vaccines comprising the heroin immunoconjugates in active or passive immunization protocols. The compositions and methods of the invention are useful for prevention and treatment of heroin addiction.
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DIFLUOROMETHYLATION OF UNSATURATED COMPOUNDS (Fri, 07 Jun 2013)
A reagent for carrying out a difluoromethylation reaction of unsaturated compounds and ring-nitrogen-containing aromatic compounds, a zinc difluoro-methanesulfinate, as well as a method for making the reagent and a method for its use are disclosed.
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SYNTHESIS OF LIBRARIES OF PEPTIDE TERTIARY AMIDES (Fri, 03 May 2013)
The present disclosure is directed to a novel class of peptide-like oligomers called peptide tertiary amides (PTAs),and a combinatorial library of PTAs along with synthetic routes for the preparation of large combinatorial libraries of these compounds. The peptide tertiary amides provide an exceptional source of high affinity and selective protein ligands that are useful as tools for biological research and as drug leads, among others.
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AN HIV-1 GP120 MINI V3 LOOP AND USES THEREOF (Fri, 19 Apr 2013)
The invention relates to an immunogenic HIV-1 gp120 mini V3 loop, which is a truncated version of the full-length gp120 V3 loop useful for crystallization with antibodies that recognize carbohydrate moieties. The invention also relates to the structure of a broadly neutralizing antibody as a complex with a glycosylated gp120 outer domain, as determined by crystallographic techniques, and the confirmation that a glycosylated gp120 outer domain has a functional relevant conformation, as well as the determination of key residues on a glycosylated gp120 outer domain, and uses thereof and compounds and compositions therefrom. Furthermore, the invention also relates to other peptides and mimetic peptides, which bind to broadly neutralizing antibodies.
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KAPPA OPIOID RECEPTOR EFFECTORS AND USES THEREOF (Fri, 22 Mar 2013)
The present invention is a selective kappa opioid receptor effector, or a pharmaceutically acceptable salt thereof, useful for treating ethanol use disorder withdrawal, anxiety and/or depression, schizophrenia, mania or post-traumatic stress disorder.
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MOLECULAR CATALYSTS FOR N2 CONVERSIONS AT LOWER TEMPERATURES AND PRESSURES (Fri, 15 Mar 2013)
The present invention is directed in various embodiments to catalysts and methods for activation of dinitrogen N2, (e.g., nitrogen gas) such as for reduction of N2 with a reductant in the presence of the catalyst to ammonia NH3, or conversion to nitrogen-containing products such as urea and amines. In various embodiments, the invention provides methods of preparation of ammonia and other nitrogen-containing products from nitrogen gas in the presence of a reductant such as hydrogen gas, under conditions of relatively low temperature and low pressure compared with temperatures and pressures used in art methods of nitrogen fixation (reduction). Catalysts of the invention are molecular, i.e., not heterogeneous, catalysts, soluble in a solvent medium comprising a strong base and a liquid solvent.
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MODULATORS OF REV-ERB (Fri, 08 Mar 2013)
The subject matter herein concerns the identification and development of potent synthetic REV-ERB ligands, such as in vivo agonists and antagonists. These compounds allow for characterization of the effects of modulation of this receptor in vivo specifically on circadian behavior and metabolism, and have suitable characteristics for development of medicinal compounds useful for treatment of malconditions such as diabetes, obesity, atherosclerosis, dyslipidemia, a circadian rhythm disorder, coronary artery disease, bipolar disorder, depression, cancer, a sleep disorder, an anxiety disorder, an addiction disorder, or an autoimmune disorder.
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GLYCOPEPTIDE ANTIBIOTIC ANALOGS EFFECTIVE AGAINST VANCOMYCIN-RESISTANT BACTERIAL STRAINS (Fri, 15 Feb 2013)
The invention is directed to glycopeptide antibiotics and their aglycones that are engineered to overcome bacterial resistance by replacement of a single, specific peptide carboxamide group in the core peptide of the glycopeptide antibiotic with an amidine group. The amidine pseudopeptide analog of the glycopeptide is effective in killing vancomycin-resistant bacteria at therapeutically achievable concentrations in a patient. For example, a [ψ[C(=NH)NH]Tpg4]-vancomycin aglycon designed to exhibit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria has been shown to overcome a common mode of bacterial resistance to the "last resort" antibiotics of the glycopeptide class. The pseudopeptide amidine analogs can be prepared from corresponding pseudopeptide thioamide analogs, which can be prepared synthetically, semi-synthetically, or biosynthetically.
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Modulators of sphingosine phosphate receptors (Fri, 28 Dec 2012)
<p id="p-0001" num="0000">Compounds of the following generic structure are provided:</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="23.79mm" wi="40.81mm" file="US08466183-20130618-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> Such compounds activate a sphingosine-I-phosphate receptor of the subtype 1 (S1P1), and have utility in the treatment of malconditions mediated by S1P1 activation. More specifically, such compounds are beneficial in the treatment of, for example, multiple sclerosis, transplant rejection and/or adult respiratory syndrome. </p>
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Modulators of sphingosine phosphate receptors (Fri, 28 Dec 2012)
<p id="p-0001" num="0000">Compounds of the following generic structure are provided:</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="23.79mm" wi="41.66mm" file="US08481573-20130709-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> Such compounds activate a sphingosine-I-phosphate receptor of the subtype 1 (S1P1), and have utility in the treatment of malconditions mediated by S1P1 activation. More specifically, such compounds are beneficial in the treatment of, for example, multiple sclerosis, transplant rejection and/or adult respiratory syndrome. </p>
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Modulators of sphingosine phosphate receptors (Fri, 28 Dec 2012)
<p id="p-0001" num="0000">Compounds of the following generic structure are provided:</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="23.79mm" wi="42.16mm" file="US08530503-20130910-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> Such compounds activate a sphingosine-I-phosphate receptor of the subtype 1 (S1P1), and have utility in the treatment of malconditions mediated by S1P1 activation. More specifically, such compounds are beneficial in the treatment of, for example, multiple sclerosis, transplant rejection and/or adult respiratory syndrome. </p>
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N-BENZYLINDOLE MODULATORS OF PPARG (Fri, 14 Dec 2012)
The invention provides molecular entities that bind with high affinity to PPARG (PPARγ), and inhibit kinase-mediated (e.g., cdk5-mediated) phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. Side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, can be avoided in the mammal receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.
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MODULATORS OF THE NUCLEAR HORMONE RECEPTOR ROR (Fri, 23 Nov 2012)
The invention provides small molecule modulators of retinoic acid receptor-related orphan receptors such as RORα, RORβ, or RORγ. Compounds of the invention can be effective modulators at concentrations ineffective to act on LXR receptors, or on other nuclear receptors, or other biological targets. Methods of modulation the RORs and methods of treating metabolic disorders, immune disorders, cancer, and CNS disorders wherein modulation of an ROR is medically indicated are also provided.
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Tyrosine bioconjugation through aqueous Ene-like reactions (Fri, 16 Nov 2012)
<p id="p-0001" num="0000">A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an Ene-like reaction is reported. This mild aqueous tyrosine ligation reaction works over a broad pH range and expands the repertoire of aqueous chemistries available for small molecule, peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in buffered aqueous solution. This reaction provides a novel synthetic approach to bispecific antibodies. This reaction will find broad utility in peptide and protein chemistry and in the chemistry of phenol-containing compounds.</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="98.30mm" wi="75.86mm" file="US08765920-20140701-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p>
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Expanding the eukaryotic genetic code (Fri, 09 Nov 2012)
<p id="p-0001" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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Small molecules that covalently modify transthyretin (Fri, 26 Oct 2012)
<p id="p-0001" num="0000">A family of covalent kinetic stabilizer compounds that selectively and covalently react with the prominent plasma protein transthyretin in preference to more than 4000 other human plasma proteins is disclosed. A contemplated compound corresponds in structure to Formula I, below, where the various substituents are defined within, and</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="45.38mm" wi="69.85mm" file="US08703815-20140422-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> <br/> reacts chemoselectively with one or two of four Lys-15 ε-amino groups within the transthyretin tetramer. The crystal structure confirms the binding orientation of the compound substructure and the conjugating amide bond. A covalent transthyretin kinetic stabilizer exhibits superior amyloid inhibition potency, compared to a non-covalent counterpart, and inhibits cytotoxicity associated with amyloidogenesis. </p>
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Modified-galactosyl ceramides for staining and stimulating natural killer T cells (Fri, 26 Oct 2012)
<p id="p-0001" num="0000">Modified glycolipid compounds are provided. Also disclosed are methods for activating an NKT cell, methods of stimulating an immune response in a subject, and methods suitable for labeling NKT cells.</p>
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Human aminoacyl-tRNA synthetase polypeptides useful for the regulation of angiogenesis (Fri, 19 Oct 2012)
<p id="p-0001" num="0000">Pharmaceutical compositions comprising truncated tryptophanyl-tRNA synthetase polypeptides useful for regulating angiogenesis an nucleic acids encoding such tRNA synthetase polypeptides are described. Methods of making and using such compositions are also disclosed.</p>
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Glycolipids and analogues thereof as antigens for NKT cells (Fri, 12 Oct 2012)
<p id="p-0001" num="0000">This invention relates to immunogenic compounds which serve as ligands for NKT (natural killer T) cells and to methods of use thereof in modulating immune responses.</p>
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N1- AND N2-CARBAMOYL-1,2,3-TRIAZOLE SERINE HYDROLASE INHIBITORS AND METHODS (Fri, 12 Oct 2012)
The present invention provides inhibitors of a wide variety of serine hydrolase enzymes. The inhibitors of the present invention are N1- and N2-carbamoyl-1,2,3-triazole compounds such as those of Formula (I): (Formula (I)) in which N1, N2 and N3 are the nitrogen atoms at positions 1, 2, and 3, respectively, of the triazole ring, and R4, R5, R6, and R7 in Formula (I) are as described herein. Methods of inhibiting serine hydrolase enzymes and methods of preparing carbamoyl-1,2,3-triazole compounds also are described.
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COMPOUNDS AND METHODS FOR INDUCING CHONDROGENESIS (Fri, 28 Sep 2012)
The present invention provides compounds and compositions for the amelioration of arthritis and joint injuries by inducing mesenchymal stem cells into chondrocytes.
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ALPHA-KETOHETEROCYCLES AND METHODS OF MAKING AND USING (Fri, 10 Aug 2012)
Compounds are disclosed that are effective in inhibition of fatty acid amide hydrolase, an enzyme responsible for catabolism of endogenous cannabinoids such as anandamide. The compounds are useful as analgesic compounds and as sleep-inducing compounds, that can be orally administered, and that can have a relatively long duration of effect. Methods of preparation of the compounds are also provided. The compounds are conformationally constrained analogs of heterocyclylketones such as oxazolylketones.
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BENZ IMIDAZOLE COMPOUNDS THAT EXPAND HEMATOPOIETIC STEM CELLS (Fri, 03 Aug 2012)
The present invention relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. The invention further relates to a cell population comprising expanded hematopoietic stem cells (HSCs) and its use in autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficient and autoimmune diseases and diverse hematopoietic disorders to reconstitute the hematopoietic cell lineages and immune system defense.
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INHIBITORS OF RETROVIRAL REPLICATION (Fri, 20 Jul 2012)
Methods for preventing or treating retroviral infection, such as human immunodeficiency virus, in vivo utilize transcriptional inhibitory compounds. These include cortistatin A and analogs of the cortistatin family.
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SYNTHESIS OF CONOLIDINE AND DISCOVERY OF A POTENT NON-OPIOID ANALGESIC FOR PAIN (Fri, 29 Jun 2012)
The first de novo synthetic pathway to the exceptionally rare C5-nor stemmadenine natural product, conolidine, and the first asymmetric synthesis of any member of this natural product class arc described. C5-nor stemmadenine compositions are also described. These compounds, for example,(+/- )-,(+)- and (-)-conolidine are potent and efficacious non-opioid analgesics in tonic and persistent pain.
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Antitoxin and vaccine platform based on nodavirus VLPS (Fri, 22 Jun 2012)
<p id="p-0001" num="0000">Antitoxin and vaccine compositions based on nodavirus VLPs are provided. Anthrax antitoxin and vaccine compositions are provided. Methods of treating toxins with VLP-based antitoxins are provided. Methods of raising an immune response with immunogen decorated VLPs are provided.</p>
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Human A<sub>2A </sub>adenosine receptor crystals and uses thereof (Fri, 18 May 2012)
<p id="p-0001" num="0000">The invention provides the structure of human A<sub>2A </sub>adenosine receptor protein bound to an antagonist. Methods of using one or more binding sites and other features of this G-protein coupled receptor to develop new therapeutics are also disclosed.</p>
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ANTI-CANCER SERINE HYDROLASE INHIBITORY CARBAMATES (Fri, 04 May 2012)
Serine hydrolases are implicated in malconditions such as cancer, central nervous system disorders, cardiovascular disorders, obesity, and metabolic disorders. Many serine hydrolases expressed in proteomic libraries are of unknown function in vivo. Compounds identified through library versus library screening can be used for treatment of malconditions associated with the specific serine hydrolase KIAA1363 (also known as AADACL1). A library of inhibitors of KIAA1363 was prepared and candidate compounds were identified as a potent inhibitors having submicromolar IC50 values. An exemplary compound of the invention was shown to be an effective inhibitor of prostate cancer pathogenesis. Other inhibitory compounds of the invention comprising fluorophore groups are shown to be effective in spatial and temporal localization of the serine hydrolase in cells and tissues.
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RELIABLE STABILIZATION OF N-LINKED POLYPEPTIDE NATIVE STATES WITH ENHANCED AROMATIC SEQUONS LOCATED IN POLYPEPTIDE TIGHT TURNS (Fri, 30 Mar 2012)
A chimeric therapeutic polypeptide of a pre-existing therapeutic polypeptide is disclosed, as are a method of enhancing folded stabilization and a pharmaceutical composition of the glycosylated chimer. The pre-existing and chimeric polypeptides have substantially the same length, substantially the same amino acid residue sequence, and exhibit at least one tight turn containing a sequence of four to about seven amino acid residues in which at least two amino acid side chains extend on the same side of the tight turn and are within less than about 7Å of each other. The chimeric therapeutic polypeptide has the sequon Aro- (Xxx)n- ( Zzz )p-Asn-Yyy-Thr/Ser [SEQ ID NO:___] within that tight turn sequence such that the side chains of the Aro, Asn and Thr/Ser amino acid residues project on the same side of the turn and are within less than about 7Å of each other. That sequon is absent from the pre-existing therapeutic polypeptide.
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BROAD SPECTRUM ANTIBIOTIC ARYLOMYCIN ANALOGS (Fri, 23 Mar 2012)
Arylomycin analogs are provided, wherein the analogs can have broad spectrum bioactivity. Resistance to the antibiotic bioactivity of natural product arylomycin in a range of pathogenic bacterial species has been found to depend upon single amino acid mutations at defined positions of bacterial Signal Peptidases (SPases), wherein the presence of a proline residue confers arylomycin resistance. Arylomycin analogs are provided herein that can overcome that resistance and provide for a broader spectrum of antibiotic bioactivity than can natural product arylomycins such as arylomycin A2. Methods for determining if a bacterial strain is susceptible to narrow spectrum arylomycin antibiotics, or if a broad spectum analog is required for treatment, is provided. Pharmaceutical compositions and methods of treatment of bacterial infections, and methods of synthesis of arylomycin analogs, are provided.
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Methods for treating transthyretin amyloid diseases (Fri, 16 Mar 2012)
<p id="p-0001" num="0000">Kinetic stabilization of the native state of transthyretin is an effective mechanism for preventing protein misfolding. Because transthyretin misfolding plays an important role in transthyretin amyloid diseases, inhibiting such misfolding can be used as an effective treatment or prophylaxis for such diseases. Treatment methods are disclosed.</p>
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NANOPARTICLE-BASED TUMOR-TARGETED DRUG DELIVERY (Fri, 09 Mar 2012)
The present invention provides an aqueous tumor-targeting liposome nanoparticle composition comprising an aqueous dispersion of liposome nanoparticles. The nanoparticles preferably encapsulate an anti-cancer chemotherapeutic agent, which can be added to a pre-formed liposome composition or can be incorporated in the liposomes during the formation of the liposomes. The liposome nanoparticles comprise a legumain-targeting lipid admixed with one or more other micelle or vesicle-forming lipid materials in the form of nanoparticulate liposomes dispersed in an aqueous carrier. A preferred tumor-targeting liposome nanoparticle composition comprises (a) a legumain-targeting lipid component, (b) a zwitterionic lipid component; (c) an amino-substituted lipid component; (d) a neutral lipid component; and (e) polyethylene glycol-conjugated lipid component. The legumain-targeting lipid component comprising a hydrophobic lipid portion covalenetly attached to a legumain-binding moiety.
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HUMAN IMMUNODEFICIENCY VIRUS (HIV)-NEUTRALIZING ANTIBODIES (Fri, 09 Mar 2012)
The invention provides a method for obtaining a broadly neutralizing antibody (bNab), including screening memory B cell cultures from a donor PBMC sample for neutralization activity against a plurality of HIV-1 species, cloning a memory B cell that exhibits broad neutralization activity; and rescuing a monoclonal antibody from that memory B cell culture. The resultant monoclonal antibodies may be characterized by their ability to selectively bind epitopes from the Env proteins in native or monomeric form, as well as to inhibit infection of HIV-1 species from a plurality of clades. Compositions containing human monoclonal anti-HIV antibodies used for prophylaxis, diagnosis and treatment of HIV infection are provided. Methods for generating such antibodies by immunization using epitopes from conserved regions within the variable loops of gpl20 are provided. Immunogens for generating anti-HIVl bNAbs are also provided. Furthermore, methods for vaccination using suitable epitopes are provided.
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Method of stimulating NKT with 6″-amino-6″-deoxygalactosylceramides (Fri, 03 Feb 2012)
<p id="p-0001" num="0000">This invention relates to galactosylceramide compounds.</p>
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Unnatural reactive amino acid genetic code additions (Fri, 06 Jan 2012)
<p id="p-0001" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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Site specific incorporation of keto amino acids into proteins (Fri, 30 Dec 2011)
<p id="p-0001" num="0000">Compositions and methods of producing components of protein biosynthetic machinery that include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, and orthogonal pairs of tRNAs/synthetases, which incorporate keto amino acids into proteins are provided. Methods for identifying these orthogonal pairs are also provided along with methods of producing proteins with keto amino acids using these orthogonal pairs.</p>
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Chemically programmed vaccination (Fri, 23 Dec 2011)
<p id="p-0001" num="0000">Provided herein is a method for chemically programmed vaccination. Methods include inducing a covalent-binding polyclonal antibody response in a subject and programming the polyclonal response with a targeting compound.</p>
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Production of carrier-peptide conjugates using chemically reactive unnatural amino acids (Fri, 23 Dec 2011)
<p id="p-0001" num="0000">Provided are methods of making carrier polypeptide that include incorporating a first unnatural amino acid into a carrier polypeptide variant, incorporating a second unnatural amino acid into a target polypeptide variant, and reacting the first and second unnatural amino acids to produce the conjugate. Conjugates produced using the provided methods are also provided. In addition, orthogonal translation systems in methylotrophic yeast and methods of using these systems to produce carrier and target polypeptide variants comprising unnatural amino acids are provided.</p>
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Stem cell cultures (Fri, 02 Dec 2011)
<p id="p-0001" num="0000">The present invention relates compounds for stabilizing cells and methods of their use.</p>
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Methods and compositions related to targeting monoacylglycerol lipase (Fri, 11 Nov 2011)
<p id="p-0001" num="0000">This invention provides compounds that selectively inhibit monoacylglycerol lipase (MAGL). The invention also provides methods of using the MAGL selective inhibitors to stimulate 2-Arachidonoylglycerol (2-AG) mediated endocannabinoid signaling in vivo, and to treat conditions that are associated with or linked to endocannabinoid signaling. The invention additionally provides methods of treating cancer or inhibiting tumor growth by targeting MAGL with MAGL specific inhibitors. The invention further provides methods of screening for MAGL inhibitors with improved biochemical and pharmaceutical properties.</p>
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Genetic incorporation of 3-aminotyrosine into reductases (Fri, 28 Oct 2011)
<p id="p-0001" num="0000">This invention provides reductase proteins that comprise NH<sub>2</sub>Y unnatural amino acid residues, systems of orthogonal elements for incorporating NH<sub>2</sub>Y into reductases and methods of using NH<sub>2</sub>Y amino acid residues in reductases as molecular probes for probing reductases function, structure and activity.</p>
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Methods of identifying a modulator that inhibits the binding between Epstein-Barr virus induced receptor 2 and cholesterol derived ligands (Fri, 07 Oct 2011)
<p id="p-0001" num="0000">The present invention relates to modulators of the interaction between Epstein-Barr Virus induced receptor-2 (EBi2) and cholest-5-ene-3b,7b,25-triol (7,25-dihydroxycholesterol) (“7,25DHC”) and/or cholest-5-ene-3b, 7b-diol (7-hydroxycholesterol) (“7HC”). The modulator maybe a small chemical molecule, antibody or other therapeutic protein. Methods of medical treatment and methods of identifying modulators are also described.</p>
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COMPOSITIONS AND METHODS FOR TREATMENT OF NEURODEGENERATIVE DISEASE (Fri, 30 Sep 2011)
Compounds, compositions, kits and methods for treating conditions related to neurodegeneration or ocular disease, are disclosed.
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Crystal of a cytochrome-ligand complex and methods of use (Fri, 23 Sep 2011)
<p id="p-0001" num="0000">The teachings relates to the three-dimensional structure of a crystal of a cytochrome protein complexed with a ligand. The three-dimensional structure of four cytochrome P450 2A6-ligand complexes are disclosed. Cytochrome P450 2A6-ligand crystal structures, wherein the ligand is an inhibitor molecule, are useful for providing structural information that may be integrated into drug screening and drug design processes. Thus, the teachings also relate to methods for utilizing a crystal structure of a cytochrome P450 2A6-ligand complex for identifying, designing, selecting, or testing inhibitors of the cytochrome protein. Such inhibitors are useful as therapeutics for the treatment or modulation of i) diseases; ii) disease symptoms; or iii) the effect of other physiological events mediated by the cytochrome.</p>
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MODULATORS OF THE RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTORS (Fri, 23 Sep 2011)
The invention provides small molecule modulators of retinoic acid receptor-related orphan receptors such as RORα RORβ, or RORγ. Compounds of the invention can be effective modulators at concentrations ineffective to act on LXR receptors, or on other nuclear receptors, or other biological targets. Methods of modulation the RORs and methods of treating metabolic disorders, immune disorders, cancer, and CNS disorders wherein modulation of an ROR is medically indicated are also provided.
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Stem cell cultures (Fri, 16 Sep 2011)
<p id="p-0001" num="0000">The present invention relates compounds for stabilizing cells and methods of their use.</p>
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Expanding the eukaryotic genetic code (Fri, 09 Sep 2011)
<p id="p-0001" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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10'-FLUORINATED VINCA ALKALOIDS PROVIDE ENHANCED BIOLOGICAL ACTIVITY AGAINST MDR CANCER CELLS (Fri, 26 Aug 2011)
A 10'-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt is disclosed, as are methods of its preparation and use. A disclosed 10'-fluoro-vinca alkaloid compound has better cytotoxic potency against leukemia and cancer cell lines, and is about 8-times more cytotoxic to a multiple drug resistant cancer cell line than is a parental 10'-unsubstituted vinca alkaloid.
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10'-FLUORINATED VINCA ALKALOIDS PROVIDE ENHANCED BIOLOGICAL ACTIVITY AGAINST MDR CANCER CELLS (Fri, 26 Aug 2011)
A 10'-fluoro-vinca alkaloid compound or its pharmaceutically acceptable salt is disclosed, as are methods of its preparation and use. A disclosed 10'-fluoro-vinca alkaloid compound has better cytotoxic potency against leukemia and cancer cell lines, and is about 8-times more cytotoxic to a multiple drug resistant cancer cell line than is a parental 10'-unsubstituted vinca alkaloid.</p>
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MONOMERIC FORMS OF HUMAN AMINOACYL-TRNA SYNTHETASES HAVING NON-CANONICAL BIOLOGICAL ACTIVITIES (Fri, 12 Aug 2011)
Isolated monomelic aminoacyl-tRNA synthetase polypeptides and polynucleotides having non-canonical biological activities are provided, as well as compositions and methods related thereto.
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ALPHA-KETO HETEROCYCLES AS FAAH INHIBITORS (Fri, 29 Jul 2011)
<p id="p-0001" num="0000">The invention provides a series of -αketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.</p>
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TYROSINE BIOCONJUGATION THROUGH AQUEOUS ENE-LIKE REACTIONS (Fri, 01 Jul 2011)
A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an Ene-like reaction is reported. This mild aqueous tyrosine ligation reaction works over a broad pH range and expands the repertoire of aqueous chemistries available for small molecule, peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in buffered aqueous solution. This reaction provides a novel synthetic approach to bispecific antibodies. This reaction will find broad utility in peptide and protein chemistry and in the chemistry of phenol-containing compounds.
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TYROSINE BIOCONJUGATION THROUGH AQUEOUS ENE-LIKE REACTIONS (Fri, 01 Jul 2011)
A new and versatile class of cyclic diazodicarboxamides that reacts efficiently and selectively with phenols and the phenolic side chain of tyrosine through an Ene-like reaction is reported. This mild aqueous tyrosine ligation reaction works over a broad pH range and expands the repertoire of aqueous chemistries available for small molecule, peptide, and protein modification. The tyrosine ligation reactions are shown to be compatible with the labeling of native enzymes and antibodies in buffered aqueous solution. This reaction provides a novel synthetic approach to bispecific antibodies. This reaction will find broad utility in peptide and protein chemistry and in the chemistry of phenol-containing compounds.</p>
>> read more

BENZOPYRANS AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 24 Jun 2011)
<p id="p-0001" num="0000">Compounds useful as Rho kinase inhibitors of formula (1) wherein the variables are as defined herein are provided. Methods of treatment of malconditions mediated by Rho kinase, and methods of preparation of the compounds, are also provided.</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="37.59mm" wi="58.08mm" file="US20110150833A1-20110623-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p>
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SMALL MOLECULES THAT COVALENTLY MODIFY TRANSTHYRETIN (Fri, 24 Jun 2011)
A family of covalent kinetic stabilizer compounds that selectively and covalently react with the prominent plasma protein transthyretin in preference to more than 4000 other human plasma proteins is disclosed. A contemplated compound corresponds in structure to Formula I, below, where the various substituents are defined within, and reacts chemoselectively with one or two of four Lys-15 ε-amino groups within the transthyretin tetramer. The crystal structure confirms the binding orientation of the compound substructure and the conjugating amide bond. A covalent transthyretin kinetic stabilizer exhibits superior amyloid inhibition potency, compared to a non-covalent counterpart, and inhibits cytotoxicity associated with amyloidogenesis.
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CADHERIN MODULATORY AGENTS (Fri, 17 Jun 2011)
Compositions are provided comprising agents such as small molecules that modulate the biological activity of cadherins, the angiostatic activity of tryptophanyl-tRNA synthetases (WRS), or both. Also provided are methods of using such compositions for modulating cadherin-mediated activities, such as angiogenesis, and for treating conditions associated with these activities.
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NUCLEIC ACID ENCODING TRUNCATED TRYPTOPHANYL TRNA SYNTHETASE (Wed, 01 Jun 2011)

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Human aminoacyl-tRNA synthetase polypeptides useful for the regulation of angiogenesis (Fri, 13 May 2011)
<p id="p-0001" num="0000">Compositions comprising truncated tryptophanyl-tRNA synthetase polypeptides useful for regulating angiogenesis, as well as nucleic acids encoding such tRNA synthetase polypeptides are described. Methods of making and using such compositions are also disclosed.</p>
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Glycolipids and analogues thereof as antigens for NKT cells (Fri, 15 Apr 2011)
<p id="p-0001" num="0000">This invention relates to immunogenic compounds which serve as ligands for NKT (natural killer T) cells and to methods of use thereof in modulating immune responses.</p>
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METHODS OF ACTIVATING NKT CELLS (Fri, 08 Apr 2011)
<p id="p-0001" num="0000">Provided are methods of activating an NKT cell which include a step of contacting the NKT cell with a sufficient amount of isoglobotrihexosylceramide (iGb3) to induce secretion of a cytokine from the NKT cell, stimulate proliferation of the NKT cell or upregulate expression of a cell surface marker on the NKT cell. Methods of activating an NKT cell population in a subject are also provided.</p>
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Protein arrays (Fri, 01 Apr 2011)
<p id="p-0001" num="0000">The invention provides proteins attached to solid supports, and methods of preparing such solid support-bound proteins are provided. The proteins are attached to solid supports by means of an unnatural amino acid incorporated into the protein, which unnatural amino acid includes a reactive group that can react with a second reactive group that is attached to a solid support.</p>
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PD(II)-CATALYZED HYDROXYLATION OF ARENES WITH O2 OR AIR (Fri, 01 Apr 2011)
Pd (II) -catalyzed ortho-hydroxylat ion of variously substituted aromatic carboxylic acids under O2 or air is achieved under non-acidic conditions. Extensive labeling studies support a direct oxygenation of aryl C-H bonds with molecular oxygen.
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NICOTINE HAPTENS, IMMUNOCONJUGATES AND THEIR USES (Fri, 18 Mar 2011)
The present invention provides novel nicotine hapten compounds and nitocine immunoconjugates which can be used for in vivo production of antibodies that specifically bind to nicotine. The invention also provides methods of using vaccines comprising the nicotine immunoconjugates in active or passive immunization protocols. The compositions and methods of the invention are useful for prevention and treatment of nicotine addiction.
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METHOD OF PREPARING GLYCOPEPTIDES (Fri, 11 Mar 2011)
<p id="p-0001" num="0000">A method is provided for the synthesis of glycopeptides using a sugar assisted ligation strategy, wherein an N-terminal peptide portion in the form of a thioester is coupled with a C-terminal peptide portion bearing a carbohydrate moiety comprising a thiol group.</p>
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Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid (Fri, 04 Mar 2011)
<p id="p-0001" num="0000">The present invention comprises methods and compositions for producing and/or enhancing an immunological response in a subject against a target moiety such as a disease-related moiety by administration of an antigenic version of the target moiety having one or more unnatural amino acid and/or by administration of an antibody against a version of a target moiety having one or more unnatural amino acid which antibody is cross reactive with the natural target moiety.</p>
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BENZIMIDAZOLES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 04 Mar 2011)
<p id="p-0001" num="0000">Compounds useful as Rho kinase inhibitors according to formula IA or IB: wherein A, B, D, E, R<sup>1</sup>, R<sup>2 </sup>and Ar<sup>1 </sup>are as defined herein, and any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof, pharmaceutical compositions, methods of treatment, and synthetic methods are provided.</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="51.73mm" wi="58.59mm" file="US20110052562A1-20110303-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p>
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METHOD OF PRODUCING A PROTEIN IN A CELL WITH P-ACETYL-L-PHENYLALANINE AT A SPECIFIED POSITION (Tue, 01 Mar 2011)

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Inhibitors of focal adhesion kinase (Fri, 25 Feb 2011)
<p id="p-0001" num="0000">The invention provides inhibitors of focal adhesion kinase, an enzyme involved in the attachment of the cytoskeleton of a cell to an extracellular matrix, which has been implicated in processes such as cell migration, cell proliferation, and cell survival. The inhibitors are derivatives of a 5-substituted 2,4-diaminopyridine wherein the substituents are as defined herein. The invention also provides a method of using the inhibitors in treatment of cancer, and methods of preparation of the inhibitors by use of coupling reactions.</p>
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ANILIDES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 18 Feb 2011)
<p id="p-0001" num="0000">Compounds useful as Rho kinase inhibitors of formula (I): wherein variable are as defined herein are provided. Methods of treatment of malconditions mediated by Rho kinase, and methods of preparation of the compounds, are also provided.</p> <p id="p-0002" num="0000"><chemistry id="CHEM-US-00001" num="00001"> <img id="EMI-C00001" he="36.07mm" wi="54.44mm" file="US20110038835A1-20110217-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p>
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COPPER CATALYZED CYCLOADDITION OF ORGANIC AZIDES AND 1-HALOALKYNES (Fri, 18 Feb 2011)
This invention provides a method for preparing a 1,2,3-triazole compound comprising contacting an organic azide with a 2-substitued-1-haloalkyne, in the presence of a copper catalyst and a copper-coordinating ligand (preferably a tertiary amine) in a liquid reaction medium, thereby forming a 1,4,5-substituted-1,2,3-triazole compound including a halo substituent at the 5-position of the triazole, the organic portion of the organic azide at the 1-position of the triazole, and the substituent of the 1-iodoalkyne at the 4-position of the triazole. A method for preparing 1-iodoalkynes is also provided.
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Methods and compositions for obtaining high-resolution crystals of membrane proteins (Fri, 11 Feb 2011)
<p id="p-0001" num="0000">The invention describes compositions and method useful for the crystallization of membrane proteins.</p>
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In vivo unnatural amino acid expression in the methylotrophic yeast <i>Pichia pastoris </i> (Fri, 21 Jan 2011)
<p id="p-0001" num="0000">The invention provides orthogonal translation systems for the production of polypeptides comprising unnatural amino acids in methylotrophic yeast such as Pichia pastoris. Methods for producing polypeptides comprising unnatural amino acids in methylotrophic yeast such as <i>Pichia pastoris </i>are also provided.</p>
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COMPOUNDS AND METHODS FOR CHELATING METALS IN AQUEOUS SOLUTIONS (Fri, 03 Dec 2010)
The present invention relates to a new class of organic compounds and their use, for example, to sequester metal ions, including actinides (such as uranium and plutonium), precious metals (such as gold, silver and platinum) and all other metals (such as transition metals), from aqueous solutions, such as bodies of water (including but not limited to ocean water, seawater, river water) and all other aqueous solutions. Specifically, the present invention relates to a new class of polydentate organic chelating agents and methods for their use to recover metals from aqueous solutions, such as uranium from seawater.
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Substituted pyrimidinyl-amines as protein kinase inhibitors (Fri, 26 Nov 2010)
<p id="p-0001" num="0000">The present invention provides novel substituted pyrimidinyl-amines that are useful as inhibitors of protein kinases, especially c-Jun N-terminal kinases (JNK) and pharmaceutical compositions thereof and methods of using the same for treating conditions responsive to the inhibition of the JNK pathway.</p>
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Production of carrier-peptide conjugates using chemically reactive unnatural amino acids (Fri, 26 Nov 2010)
<p id="p-0001" num="0000">Provided are methods of making carrier polypeptide that include incorporating a first unnatural amino acid into a carrier polypeptide variant, incorporating a second unnatural amino acid into a target polypeptide variant, and reacting the first and second unnatural amino acids to produce the conjugate. Conjugates produced using the provided methods are also provided. In addition, orthogonal translation systems in methylotrophic yeast and methods of using these systems to produce carrier and target polypeptide variants comprising unnatural amino acids are provided.</p>
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METHODS FOR ENHANCING INFECTIVITY OF RETROVIRUSES (Fri, 26 Nov 2010)
The present invention provides methods for producing retroviruses or viral vectors with enhanced infectivity. The methods entail transfecting a retroviral vector into a packaging cell that has suppressed expression or inhibited enzymatic activity of a parvulin prolyl peptidyl isomerase (parvulin PPIase), and culturing the transfected packaging cell to allow production of viral particles. The invention also provides methods for enhancing efficiency of gene transfer with a recombinant retrovirus. These methods involve constructing a recombinant retroviral vector expressing a target gene, transfecting into a packaging cell that has suppressed expression or inhibited enzymatic activity of a parvulin prolyl peptidyl isomerase (parvulin PPIase), culturing the transfected packaging cell to allow production of recombinant retroviral particles, harvesting recombinant retroviral particles from supernatant of the cultured cell, and transducing the recombinant retroviral particles into a target cell. Kits for carrying out these methods are also provided in the invention.
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Ruthenium-catalyzed cycloaddition of alkynes and organic azides (Fri, 12 Nov 2010)
<p id="p-0001" num="0000">A convenient process for the regioselective synthesis of 1,5-disubstituted 1,2,3-triazoles and 1,4,5-trisubstituted 1,2,3-triazoles from organic azides and alkynes employs catalytic ruthenium.</p>
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Enhanced Indolinone Based Protein Kinase Inhibitors (Fri, 22 Oct 2010)
<p id="p-0001-en" num="0000">Alpha-hydroxy-omega-(2-oxo-indolylidenemethyl-pyrrole-3′-carbonyl)amino alkanoic acid and amide derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.</p>
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PALLADIUM-CATALYZED ORTHO-FLUORINATION (Fri, 08 Oct 2010)
A new method of ortho-fluorination where an aryl C-H bond is directly replaced by an aryl C-F bond in a palladium-catalyzed reaction is provided. The method includes the ortho-fluorination of a triflamide protected benzylamine, a palladium catalyst, such as Pd(OTf)2, a fluorinating reagent such as N-fluoro-2,4,6-trimethylpyridinium triflate, and a ligand to promote the reaction such as N-methylpyrrolidinone (NMP).
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A FACILE SYSTEM FOR ENCODING UNNATURAL AMINO ACIDS IN MAMMALIAN CELLS (Fri, 08 Oct 2010)
This invention provides translation system components functional in both eubacterial and eukaryotic environments. The translation system components, such as aminoacyl-tRNA synthetases and tRNAs derived from Methanosarcina species are capable of charging unnatural amino acids, and can be shuttled from enterobacteria to mammalian cells.
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Tetracyclic inhibitors of fatty acid amide hydrolase (Fri, 01 Oct 2010)
<p id="p-0001" num="0000">Certain tetracyclic compounds are described, which may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).</p>
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Small Molecule Mimetics of Erythropoietin (Fri, 01 Oct 2010)
<p id="p-0001-en" num="0000">The invention features computer-assisted methods for identifying molecules which will bind to the EPO receptor and act as an erythropoietin (EPO) mimetic. Preferred EPO mimetics identified using the method of the invention act as agonists of the EPO receptor in one or more in vitro or in vivo biological assays of EPO activity.</p>
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HUMAN IMMUNODEFICIENCY VIRUS (HIV) -NEUTRALIZING ANTIBODIES (Fri, 24 Sep 2010)
The invention provides a method for obtaining a broadly neutralizing antibody (bNab), including screening memory B cell cultures from a donor PBMC sample for neutralization activity against a plurality of HIV-I species, cloning a memory B cell that exhibits broad neutralization activity; and rescuing a monoclonal antibody from that memory B cell culture. The resultant monoclonal antibodies are characterized by their ability to selectively bind epitopes from the Env proteins in native or monomeric form, as well as to inhibit infection of HIV-I species from a plurality of clades. Compositions containing human monoclonal anti-HIV antibodies used for prophylaxis, diagnosis and treatment of HIV infection are provided. Methods for generating such antibodies by immunization using epitopes from conserved regions within the variable loops of gpl20 are provided. Immunogens for generating anti-HIV 1 bNAbs are also provided. Furthermore, methods for vaccination using suitable epitopes are provided.
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HUMAN IMMUNODEFICIENCY VIRUS (HIV) -NEUTRALIZING ANTIBODIES (Fri, 24 Sep 2010)
The invention provides a method for obtaining a broadly neutralizing antibody (bNab), including screening memory B cell cultures from a donor PBMC sample for neutralization activity against a plurality of HIV-I species, cloning a memory B cell that exhibits broad neutralization activity; and rescuing a monoclonal antibody from that memory B cell culture. The resultant monoclonal antibodies are characterized by their ability to selectively bind epitopes from the Env proteins in native or monomeric form, as well as to inhibit infection of HIV-I species from a plurality of clades. Compositions containing human monoclonal anti-HIV antibodies used for prophylaxis, diagnosis and treatment of HIV infection are provided. Methods for generating such antibodies by immunization using epitopes from conserved regions within the variable loops of gpl20 are provided. Immunogens for generating anti-HIV 1 bNAbs are also provided. Furthermore, methods for vaccination using suitable epitopes are provided. </p>
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COMPOUNDS THAT MAINTAIN PLURIPOTENCY OF EMBRYONIC STEM CELLS (Fri, 17 Sep 2010)
<p id="p-0001-en" num="0000">The present invention relates to methods and compositions for culturing embryonic stem (ES) cells. The methods relate to growing the ES cells in the presence of small molecules of formula (I) that maintain the pluripotency/self-renewal of the cells without feeder cells and LIF in serum-free conditions. These methods in part facilitate much more consistency in embryonic stem cell production, providing, for example, new avenues in the practical applications of embryonic stem cells in regenerative medicine.</p> <p id="p-0002-en" num="0000"> <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001" he="31.75mm" wi="75.78mm" file="US20100234400A1-20100916-C00001.TIF" img-content="chem" img-format="tif"/> </chemistry> </p>
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Tricyclic inhibitors of fatty acid amide hydrolase (Fri, 27 Aug 2010)
<p id="p-0001" num="0000">A series of substituted oxazole compounds having an alpha keto side chain at the 2 position and an aromatic, heteroaromatic or heterocycle substituent at the 5 position are disclosed. These compounds exhibit inhibition of fatty acid amid hydrolase and arc useful for treatment of malconditions involving that enzyme.</p>
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CHEMICALLY PROGRAMMED VACCINATION (Fri, 20 Aug 2010)
Provided herein is a method for chemically programmed vaccination. Methods include inducing a covalent-binding polyclonal antibody response in a subject and programming the polyclonal response with a targeting compound.
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Ligands for copper-catalyzed azide-alkyne cycloaddition reactions (Fri, 06 Aug 2010)
<p id="p-0001" num="0000">Ligands useful for promoting copper-catalyzed azide-alkyne cycloaddition reactions comprise a compound represented by structural Formula (I) as described in the specification, wherein in Formula (I) Z<sup>1 </sup>is a nitrogen-containing heterocyclic group or a group represented by the formula: Y<sup>1</sup>—(CH<sub>2</sub>)<sub>c</sub>—Y<sup>2</sup>—(CH<sub>2</sub>)<sub>d</sub>—Y<sup>3</sup>—CH<sub>2</sub>—N(CH<sub>2</sub>Z<sup>4</sup>)(CH<sub>2</sub>Z<sup>5</sup>), where Y<sup>1 </sup>is -E<sup>1</sup>-C(O)O—, -E<sup>1</sup>-C(O)NH—, -E<sup>1</sup>-, or a covalent bond; Y<sup>2 </sup>is a covalent bond, —CH═CH—, or a 1,4-(1,2,3-triazolyl) group; Y<sup>3 </sup>is —OC(O)-E<sup>2</sup>-, —NHC(O)-E<sup>2</sup>-, -E<sup>2</sup>-, or a covalent bond; each of E<sup>1 </sup>and E<sup>2 </sup>is a benzimidazolyl group attached at the 1 and 2 positions; each of c and d is independently 1, 2, 3, 4, or 5; each of Z<sup>2</sup>, Z<sup>3</sup>, Z<sup>4 </sup>and Z<sup>5 </sup>is a nitrogen-containing heterocyclic group including a substituent X<sup>1 </sup>and optionally including a substituent (CH<sub>2</sub>)<sub>n</sub>—R<sup>1</sup>, and Y<sup>1</sup>, Y<sup>2</sup>, Y<sup>3</sup>, X<sup>1</sup>, R<sup>1</sup>, c, d and n are each as defined in the specification.</p>
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Expanding the eukaryotic genetic code (Fri, 25 Jun 2010)
<p id="p-0001-en" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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PRODUCTION OF CARRIER-PEPTIDE CONJUGATES USING CHEMICALLY REACTIVE UNNATURAL AMINO ACIDS (Fri, 18 Jun 2010)
Provided are methods of making carrier polypeptide that include incorporating a first unnatural amino acid into a carrier polypeptide variant, incorporating a second unnatural amino acid into a target polypeptide variant, and reacting the first and second unnatural amino acids to produce the conjugate. Conjugates produced using the provided methods are also provided. In addition, orthogonal translation systems in methylotrophic yeast and methods of using these systems to produce carrier and target polypeptide variants comprising unnatural amino acids are provided.
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MODULATORS OF THE INTERACTION BETWEEN CHOLESTEROL MOLECULES AND THE EPSTEIN-BARR VIRUS INDUCED RECEPTOR 2 (Fri, 18 Jun 2010)
The present invention relates to modulators of the interaction between Epstein-Barr Virus induced receptor-2 (EBI2) and cholest-5-ene-3b,7b,25-triol(7, 25- dihydroxycholesterol)(''7,25DHC'') and/orcholest-5-ene-3b, 7b-diol(7- hydroxycholesterol)(''7HC'') 25-diol (25-hydroxycholesterol)(''25HC''), especially the cholest-5-ene-3b,7a,25-triol(7a, 25-dihydroxycholesterol)(''7a,25DHC'')and/or cholest-5-ene-3b,7b,25-triol(7b, 25-dihydroxycholesterol)(''7b,25DHC'') stereoisomers. The modulator maybe a small chemical molecule, antibody or other therapeutic protein. Methods of medical treatment and methods of identifying modulators are also described.
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STEM CELL CULTURES (Fri, 11 Jun 2010)
The present invention relates compounds for stabilizing cells and methods of their use.
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STEM CELL CULTURES (Fri, 11 Jun 2010)
The present invention relates compounds for stabilizing cells and methods of their use. </p>
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6″-amino-6″-deoxygalactosylceramides (Fri, 04 Jun 2010)
<p id="p-0001" num="0000">This invention relates to galactosylceramide compounds.</p>
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COMPOUNDS THAT INDUCE PANCREATIC BETA-CELL EXPANSION (Fri, 28 May 2010)
<p id="p-0001-en" num="0000">The present invention relates to compounds and compositions for inducing the expansion of pancreatic β-cells. The invention further relates to a use of these expanded pancreatic β-cells to reversibly expand pancreatic β-cells and other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.</p>
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COMPOUNDS THAT EXPAND HEMATOPOIETIC STEM CELLS (Fri, 28 May 2010)
The present invention relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. The invention further relates to a cell population comprising expanded hematopoietic stem cells (HSCs) and its use in autologous or allogeneic transplantation for the treatment of patients with inherited immunodeficient and autoimmune diseases and diverse hematopoietic disorders to reconstitute the hematopoietic cell lineages and immune system defense.
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COMPOUNDS THAT EXPAND HEMATOPOIETIC STEM CELLS (Fri, 28 May 2010)
<br/><br/><br/><br/>The present invention relates to compounds and compositions for expanding the <br/>number of CD34+ cells for trans-plantation. <br/>The invention further relates to a cell population comprising expanded <br/>hematopoietic stem cells (HSCs) and its use in <br/>autologous or allogeneic transplantation for the treatment of patients with <br/>inherited immunodeficient and autoimmune diseases <br/>and diverse hematopoietic disorders to reconstitute the hematopoietic cell <br/>lineages and immune system defense.<br/></p>
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HETEROCYCLIC COMPOUNDS THAT INDUCE PANCREATIC BETA-CELL EXPANSION (Fri, 21 May 2010)
The present invention relates to compounds and compositions for inducing the expansion of pancreatic -cells. The invention further relates to a use of these expanded pancreatic -cells to reversibly expand pancreatic -cells and other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.
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QUINAZOLINE DERIVATIVES AS KINASE INHIBITORS (Fri, 21 May 2010)
The invention is directed to quinazoline compounds that can inhibit the bioactivity of one or more kinase enzymes, including a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof; to methods of use of those compounds; and to methods of preparation of those compounds. The inventive compounds can be used in the treatment of malconditions including cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases and benign prostatic hypertrophy (BPH), metastasis, cancer, glaucoma, ocular hypertension, retinopathy, autoimmune disease, viral infection, or myocardial pathology.
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METHODS AND COMPOSITIONS RELATED TO TARGETING MONOACYLGLYCEROL LIPASE (Fri, 21 May 2010)
This invention provides compounds that selectively inhibit monoacylglycerol lipase (MAGL). The invention also provides methods of using the MAGL selective inhibitors to stimulate 2-Arachidonoylglycerol (2-AG) mediated endocannabinoid signaling in vivo, and to treat conditions that are associated with or linked to endocannabinoid signaling. The invention additionally provides methods of treating cancer or inhibiting tumor growth by targeting MAGL with MAGL specific inhibitors. The invention further provides methods of screening for MAGL inhibitors with improved biochemical and pharmaceutical properties.
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METHODS AND COMPOSITIONS RELATED TO TARGETING MONOACYLGLYCEROL LIPASE (Fri, 21 May 2010)
This invention provides compounds that selectively inhibit monoacylglycerol lipase (MAGL). The invention also provides methods of using the MAGL selective inhibitors to stimulate 2- Arachidonoylglycerol (2-AG) mediated endocannabinoid signaling in vivo, and to treat conditions that are associated with or linked to endocannabinoid signaling. The invention additionally provides methods of treating cancer or inhibiting tumor growth by targeting MAGL with MAGL specific inhibitors. The invention further provides methods of screening for MAGL inhibitors with improved biochemical and pharmaceutical properties. </p>
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Pharmaceutically acceptable salt of 6-carboxy-2-(3,5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof (Fri, 14 May 2010)
<p id="p-0001" num="0000">Kinetic stabilization of the native state of transthyretin is an effective mechanism for preventing protein misfolding. Because transthyretin misfolding plays an important role in transthyretin amyloid diseases, inhibiting such misfolding can be used as an effective treatment or prophylaxis for such diseases. Treatment methods are disclosed.</p>
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Targeted delivery to legumain-expressing cells (Fri, 07 May 2010)
<p id="p-0001-en" num="0000">The present invention relates to new agents and methods useful for preventing, treating and diagnosing diseases such as cancer. For example, the invention relates to prodrug agents useful for targeting and delivering cytotoxic drugs to cancerous cells.</p>
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OXAZOLE-PYRIDAZINE-OXAZOLE ALPHA-HELIX MIMETIC (Fri, 07 May 2010)
<p id="p-0001-en" num="0000">There are provided alpha helix scaffolds mimicking i, i+3/i+4, i+7 or i+11 residues having the general structure oxazole-pyridazine-piperidine or oxazole-pyridazine-oxazole. The common pyridazine heterocycle originates from substituted or unsubstituted dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate. These scaffolds are synthetic counterparts of amphiphilic alpha helices having a hydrophilic face along one side and a hydrophobic face along the other side of the helix.</p>
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OXAZOLE-PYRIDAZINE-OXAZOLE ALPHA-HELIX MIMETIC (Fri, 16 Apr 2010)
There are provided alpha helix scaffolds mimicking i, i+3/i+4, i+7 or i+11 residues having the general structure oxazole-pyridazine-piperidine or oxazole-pyridazine-oxazole. The common pyridazine heterocycle originates from substituted or unsubstituted dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate. These scaffolds are synthetic counterparts of amphiphilic alpha helices having a hydrophilic face along one side and a hydrophobic face along the other side of the helix.
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Chimeric zinc finger recombinases optimized for catalysis by directed evolution (Fri, 09 Apr 2010)
<p id="p-0001" num="0000">The present invention is directed to chimeric recombinases comprising a serine recombinase operatively linked to a zinc finger nucleotide binding domain such that the chimeric recombinase protein catalyzes site-specific recombination at a DNA site specifically bound by the zinc finger nucleotide binding domain. The serine recombinase can be one of several naturally occurring serine recombinases. The invention also includes nucleic acids encoding the chimeric recombinases, vectors including the nucleic acids, host cells transformed or transfected with the vectors, methods of using the chimeric recombinases to carry out recombination, methods of using substrate-linked protein evolution to generate additional chimeric recombinases, methods of using the chimeric recombinases for gene therapy, and pharmaceutical compositions.</p>
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HUMAN A2A ADENOSINE RECEPTOR CRYSTALS AND USES THEREOF (Fri, 09 Apr 2010)
The invention provides the structure of human A2A adenosine receptor protein bound to an antagonist. Methods of using one or more binding sites and other features of this G-protein coupled receptor to develop new therapeutics are also disclosed.
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UREA AND CARBAMATE COMPOUNDS AND ANALOGS AS KINASE INHIBITORS (Fri, 02 Apr 2010)
The invention is directed to compounds that can inhibit the bioactivity of one or more kinases such as any of Rho kinases, PKB (Akt) kinases, p70S6K kinase, LIM kinases, or IKK kinases, to methods of use of those compounds, and to methods of preparation of those compounds The inventive compounds can be used In the treatment of a variety of medical malconditions.
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Substituted oxazole ketone modulators of fatty acid amide hydrolase (Fri, 26 Mar 2010)
<p id="p-0001" num="0000">Certain oxazole ketone compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).</p>
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PURINE COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS FOR THE TREATMENT OF PLASMODIUM RELATED DISEASES (Fri, 05 Mar 2010)
<p id="p-0001-en" num="0000">The invention provides a class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with kinase activity, particularly malaria.</p>
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BENZO[d]OXAZOLES AND BENZO[d]THIAZOLES AS KINASE INHIBITORS (Fri, 05 Mar 2010)
Novel benzo[d]oxazole and/or benzo[d]thiazole compounds, pharmaceutical compositions containing the benzo[d]oxazole and/or benzo[d]thiazole compounds, and methods of their pharmaceutical use are disclosed. In certain embodiments, the benzo[d]oxazole and/or benzo[d]thiazole compounds affect kinase enzyme system and can be used for the treatment of disorders in which inhibition of ROCK, PKB(Akt), p70S6K, and LIMK is medically indicated.
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Antibody catalysis of enantio- and diastereo-selective aldol reactions (Wed, 24 Feb 2010)
<p id="p-0001-en" num="0000">Nine efficient aldolase antibodies were generated using hapten 2. This hapten combines, in a single molecule, structural components employed for reactive immunization with structural components employed for forming a transition state analog of the aldol reaction. Characterization of two of these antibodies reveals that they are highly proficient (up to 1000-fold better than any other antibody catalyst) and enantioselective catalysts for aldol and retro-aldol reactions and exhibit enantio- and diastereo-selectivities opposite that of antibody 38C2.</p>
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PURINE NUCLEOTIDES ISOTOPICALLY LABELED IN THE PURINE BASE, METHODS OF MAKING THEREOF AND USES THEREOF (Fri, 12 Feb 2010)
The present invention provides purine nucleotides isotopically labeled in the purine base, methods of making thereof and uses thereof, for example, in biochemical and biophysical studies of nucleic acid structure and function. Also provided is a method of synthesizing 13C-10-formyl-tetrahydrofolate and a method of for immobilizing recombinant enzymes of the pentose phosphate pathway and the denovo purine synthesis pathway with fusion affinity domains attached to a metal chelate resin.
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ALPHA-HELIX MIMETIC WITH FUNCTIONALIZED PYRIDAZINE (Fri, 29 Jan 2010)
<p id="p-0001-en" num="0000">The synthesis of new α-helix scaffolds mimicking i, i+3 or i+4, i+7 residues, was accomplished. The common pyridazine heterocycle originates from the easily available dimethyl pyridazine-3,6-dicarboxylate building block. These scaffolds may be thought of as synthetic counterparts of amphiphilic α-helices having a hydrophilic face along one side and a hydrophobic face along the other side of the helix.</p>
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Compositions and methods for inducing cell dedifferentiation (Fri, 29 Jan 2010)
<p id="p-0001" num="0000">The present invention provides 2,6-disubstituted purine compounds, compositions and methods for dedifferentiating lineage committed mammalian cells into stem cells. The present invention also provides methods of inducing dedifferentiation of lineage committed mammalian cells into stem cells, which can be further differentiated into various lineage committed cells. Methods of identifying additional 2,6-disubstituted purine compounds useful for inducing dedifferentiation of lineage committed cells into stem cells are also provided.</p>
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ALPHA-HELIX MIMETIC WITH FUNCTIONALIZED PYRIDAZINE (Fri, 29 Jan 2010)
The synthesis of new α-helix scaffolds mimicking i, i+3 or i+4, i+7 residues, was accomplished. The common pyridazine heterocycle originates from the easily available dimethyl pyridazine-3,6-dicarboxylate building block. These scaffolds may be thought of as synthetic counterparts of amphiphilic α-helices having a hydrophilic face along one side and a hydrophobic face along the other side of the helix.
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Glycoprotein synthesis (Fri, 15 Jan 2010)
<p id="p-0001-en" num="0000">Methods for making glycoproteins, both in vitro and in vivo, are provided. One method involves incorporating an unnatural amino acid into a protein and attaching one or more saccharide moieties to the unnatural amino acid. Another method involves incorporating an unnatural amino acid that includes a saccharide moiety into a protein. Proteins made by both methods can be further modified with additional sugars.</p>
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Modulators of sphingosine phosphate receptors (Fri, 15 Jan 2010)
<p id="p-0001" num="0000">Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.</p>
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ALPHA-KETO HETEROCYCLES AS FAAH INHIBITORS (Fri, 15 Jan 2010)
The invention provides a series of -αketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.
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Methods to identify therapeutic agents (Fri, 08 Jan 2010)
<p id="p-0001-en" num="0000">As illustrated herein, cholesterol is oxidized when it is present in atherosclerotic plaques. This reaction generates cholesterol oxidation or ozonation products that can act as chemotactic attractants of macrophages, can promote differentiation of monocytes into macrophages and can increase expression of E-selectin and Class A scavenger receptor (SR-A). The present application is directed to methods of using such cholesterol ozonoation products to identify agents that can be used to treat atherosclerosis and other inflammatory artery diseases.</p>
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C4-SUBSTITUTED ALPHA-KETO OXAZOLES (Thu, 24 Dec 2009)
The invention provides a series of C4-substituted oxazole compounds having an alpha keto side chain at the 2 position, for example, compounds of formula I. The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula I, useful intermediates in the preparation of compounds of formula I, and methods of using compounds of formula I and compositions thereof.
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IN VIVO INCORPORATION OF AN UNNATURAL AMINO ACID COMPRISING A 1,2-AMINOTHIOL GROUP (Fri, 18 Dec 2009)
The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate unnatural amino acids that comprise a 1,2 aminothiol group into polypeptides. The invention provides translation systems in which polypeptides comprising unnatural amino acids that comprise a 1,2 aminothiol group can be produced. The invention also provides methods for producing polypeptides containing unnatural amino acids that comprise a 1,2 aminothiol group. Also provided by the invention are compositions comprising orthogonal aminoacyl-tRNA synthetases that preferentially aminoacylate a cognate orthogonal tRNA with unnatural amino acids that comprise a 1,2 aminothiol group. The invention provides methods for the synthesis of the unnatural amino acid 2-amino-3 -(4-(2-amino-3 -mercaptopropan-amido)phenyl)-propanoic acid.
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NOVEL MODULATORS OF SPHINGOSINE PHOSPHATE RECEPTORS (Fri, 18 Dec 2009)
Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.
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NOVEL MODULATORS OF SPHINGOSINE PHOSPHATE RECEPTORS (Fri, 18 Dec 2009)
Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided. </p>
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ALKOXY INDOLINONE BASED PROTEIN KINASE INHIBITORS (Fri, 11 Dec 2009)
<p id="p-0001-en" num="0000">Alkoxy indolinone based acid and amide derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.</p>
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Method of using click chemistry to functionalize dendrimers (Fri, 11 Dec 2009)
<p id="p-0001-en" num="0000">A library of functionalized dendritic macromolecules was prepared in extremely high yields using no protecting group strategies and with only minimal purification steps through the use of copper(I)-catalyzed 1,3-dipolar cycloaddition of azides and terminal acetylenes.</p>
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Genetically encoded fluorescent coumarin amino acids (Fri, 04 Dec 2009)
<p id="p-0001" num="0000">The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate the coumarin unnatural amino acid L-(7-hydroxycoumarin-4-yl)ethylglycine into proteins produced in eubacterial host cells such as <i>E. coli</i>. The invention provides, for example but not limited to, novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing the unnatural amino acid L-(7-hydroxycoumarin-4-yl)ethylglycine and related translation systems.</p>
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NOVEL SCAFFOLDS FOR ALPHA-HELIX MIMICRY (Fri, 04 Dec 2009)
<p id="p-0001-en" num="0000">Functionalized pyridazine derivatives having a low molecular weight and pharmaceutical compositions thereof are useful as alpha-helix mimetics and for treating conditions and/or disorders mediated by alpha-helix-binding receptors and proteins.</p>
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1,3-DIOL SYNTHESIS VIA CONTROLLED, RADICAL-MEDIATED C-H FUNCTIONALIZATION (Fri, 13 Nov 2009)
The conversion of an alcohol into a 1,3- diol via controlled, radical-mediated C-H functionalization has been demonstrated. The method entails nearly quantitative conversion of an alcohol to the corresponding N-substitutedcarbamate, followed by a variant of the Hofffman-Lδffler-Freytag reaction, cyclization, and hydrolysis to provide a 1,3-diol.
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STEREOSELECTIVE SYNTHESIS OF 17-α -AND 17-β -ARYL STEROIDAL COMPOUNDS (Fri, 13 Nov 2009)
A process for forming one or the other of a 17-α-aryl or 17-β-aryl steroidal compound in diastereo excess is disclosed. The process utilizes a 17-keto steroid to form a Δ16-17-aryl-steroid compound or a 17-β-hydroxy-17-α-aryl steroid compound that are reduced or deoxygenated, respectively, in the presence of Raney nickel to form a 17-β-aryl- steroid or 17-α-aryl steroid, respectively, in a diastereo ratio of at least 3:1.
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SYNTHESIS OF (+) CORSTISTATIN A AND RELATED COMPOUNDS (Fri, 13 Nov 2009)
An in vitro synthesis of (+) cortistatin A from readily available precursors is disclosed, as are the syntheses of related 17-aryl substituted compounds, the 17-aryl substituted compounds themselves and novel compounds useful in their preparation.
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SYNTHESIS OF (+) CORSTISTATIN A AND RELATED COMPOUNDS (Fri, 13 Nov 2009)
An in vitro synthesis of (+) cortistatin A from readily available precursors is disclosed, as are the syntheses of related 17-aryl substituted compounds, the 17-aryl substituted compounds themselves and novel compounds useful in their preparation. </p>
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Methods to identify therapeutic agents (Fri, 06 Nov 2009)
<p id="p-0001-en" num="0000">As illustrated herein, cholesterol is oxidized when it is present in atherosclerotic plaques. This reaction generates cholesterol oxidation or ozonation products that can act as chemotactic attractants of macrophages, can promote differentiation of monocytes into macrophages and can increase expression of E-selectin and Class A scavenger receptor (SR-A). The present application is directed to methods of using such cholesterol ozonation products to identify agents that can be used to treat atherosclerosis and other inflammatory artery diseases.</p>
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INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 30 Oct 2009)
<p id="p-0001-en" num="0000">Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having K<sub>i</sub>'s below 200 pM and activities 10<sup>2</sup>-10<sup>3 </sup>times more potent than the corresponding trifluoromethyl ketones. The potent inhibitors combine several features, viz.: 1.) an α-keto heterocylic head group; 2.) a hydrocarbon linkage unit employing an optimal C12-C8 chain length; and 3.) a phenyl or other π-unsaturation corresponding to the arachidonyl Δ<sup>8,9</sup>/Δ<sup>11,12 </sup>and/or oleyl Δ<sup>9,10 </sup>positions. A preferred α-keto heterocylic head group is α-keto N4 oxazolopyridine, with incorporation of a second weakly basic nitrogen. Fatty acid amide hydrolase is an enzyme responsible for the degradation of oleamide (an endogenous sleep-inducing lipid) and anandamide (an endogenous ligand for cannabinoid receptors).</p>
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Breaking immunological tolerance with a genetically encoded unnatural amino acid (Fri, 23 Oct 2009)
<p id="p-0001" num="0000">The present invention comprises methods and compositions for producing and/or enhancing an immunological response in a subject against a target moiety such as a disease-related moiety by administration of an antigenic version of the target moiety having one or more unnatural amino acid and/or by administration of an antibody against a version of a target moiety having one or more unnatural amino acid which antibody is cross reactive with the natural target moiety.</p>
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NICOTINE IMMUNOCONJUGATES (Fri, 02 Oct 2009)
Haptens and immunoconjugates useful in eliciting an immune response against nicotine are provided. The haptens may be chemically synthesized. Immunoconjugates may be formed by linking one or more haptens to a carrier molecule. Immunoconjugates may be used as a vaccine in active or passive immunization protocols.
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GLYCOLIPIDS AND ANALOGUES THEREOF AS ANTIGENS FOR NK T CELLS (Fri, 18 Sep 2009)
<p id="p-0001-en" num="0000">This invention relates to immunogenic compounds which may serve as ligands for NKT (natural killer T) cells and to methods of use thereof in modulating immune responses.</p>
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Methods and compositions for the production of orthogonal tRNA-aminoacyl-tRNA synthetase pairs (Fri, 11 Sep 2009)
<p id="p-0001" num="0000">This invention provides compositions and methods for generating components of protein biosynthetic machinery including orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, and orthogonal pairs of tRNAs/synthetases. Methods for identifying orthogonal pairs are also provided. These components can be used to incorporate unnatural amino acids into proteins in vivo.</p>
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Human aminoacyl-tRNA synthetase polypeptides useful for the regulation of angiogenesis (Fri, 11 Sep 2009)
<p id="p-0001" num="0000">Compositions comprising truncated tryptophanyl-tRNA synthetase polypeptides useful for regulating angiogenesis, as well as nucleic acids encoding such tRNA synthetase polypeptides are described. Methods of making and using such compositions are also disclosed.</p>
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Site specific incorporation of keto amino acids into proteins (Fri, 28 Aug 2009)
<p id="p-0001" num="0000">Compositions and methods of producing components of protein biosynthetic machinery that include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, and orthogonal pairs of tRNAs/synthetases, which incorporate keto amino acids into proteins are provided. Methods for identifying these orthogonal pairs are also provided along with methods of producing proteins with keto amino acids using these orthogonal pairs.</p>
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GENETIC INCORPORATION OF 3-AMINOTYROSINE INTO REDUCTASES (Fri, 21 Aug 2009)
<p id="p-0001-en" num="0000">This invention provides reductase proteins that comprise NH<sub>2</sub>Y unnatural amino acid residues, systems of orthogonal elements for incorporating NH<sub>2</sub>Y into reductases and methods of using NH<sub>2</sub>Y amino acid residues in reductases as molecular probes for probing reductases function, structure and activity.</p>
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COMPOUNDS AND COMPOSITIONS AS HEDGEHOG PATHWAY MODULATORS (Fri, 21 Aug 2009)
<p id="p-0001-en" num="0000">The invention provides a method for modulating the activity of the hedgehog signaling pathway. In particular, the invention provides a method for inhibiting aberrant growth states resulting from phenotypes such as Ptc loss-of-function, hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function, comprising contacting a cell with a sufficient amount of a compound of Formula I.</p>
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Compositions and methods for treating gram positive bacterial infection in a mammalian subject (Fri, 14 Aug 2009)
<p id="p-0001-en" num="0000">Compositions and methods are provided for treating Gram positive bacterial infection in a mammalian subject. Compositions and methods are further provided for treating Gram positive bacterial skin infection in the mammalian subject. Compositions and method are provided that comprise administering to the mammalian subject an effective amount of a compound that activates Scd1 gene expression or activates Scd1 gene product.</p>
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Methods For Treating A Condition Characterized By Dysfunction In Protein Homeostasis (Fri, 14 Aug 2009)
<p id="p-0001-en" num="0000">Methods are provided for treating conditions characterized by dysfunction in protein homeostasis in a patient in need thereof. A method for treating a condition characterized by dysfunction in protein homeostasis in a patient in need thereof is provided which comprises administering to the patient a proteostasis regulator in an amount effective to improve or restore protein homeostasis, and to reduce or eliminate the condition in the patient or to prevent its occurrence or recurrence. The condition can be a loss of function disorder such as a lysosomal storage disease, or a gain of function disorder such as an aging associated disease.</p>
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METHODS FOR TREATING A CONDITION CHARACTERIZED BY DYSFUNCTION IN PROTEIN HOMEOSTASIS (Fri, 14 Aug 2009)
Methods are provided for treating conditions characterized by dysfunction in protein homeostasis in a patient in need thereof. A method for treating a condition characterized by dysfunction in protein homeostasis in a patient in need thereof is provided which comprises administering to the patient a proteostasis regulator in an amount effective to improve or restore protein homeostasis, and to reduce or eliminate the condition in the patient or to prevent its occurrence or recurrence. The condition can be a loss of function disorder such as a lysosomal storage disease, or a gain of function disorder such as an aging associated disease.
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BREAKING IMMUNOLOGICAL TOLERANCE WITH A GENETICALLY ENCODED UNNATURAL AMINO ACID (Fri, 14 Aug 2009)
The present invention comprises methods and compositions for producing and/or enhancing an immunological response in a subject against a target moiety such as a disease-related moiety by administration of an antigenic version of the target moiety having one or more unnatural amino acid and/or by administration of an antibody against a version of a target moiety having one or more unnatural amino acid which antibody is cross reactive with the natural target moiety.
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BREAKING IMMUNOLOGICAL TOLERANCE WITH A GENETICALLY ENCODED UNNATURAL AMINO ACID (Fri, 14 Aug 2009)
The present invention comprises methods and composi-tions for producing and/or enhancing an immunological response in a sub-ject against a target moiety such as a disease-related moiety by administra-tion of an antigenic version of the target moiety having one or more unnat-ural amino acid and/or by administration of an antibody against a version of a target moiety having one or more unnatural amino acid which anti-body is cross reactive with the natural target moiety. </p>
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METHODS FOR TREATING A CONDITION CHARACTERIZED BY DYSFUNCTION IN PROTEIN HOMEOSTASIS (Fri, 14 Aug 2009)
Methods are provided for treating conditions characterized by dysfunction in protein homeostasis in a patient in need thereof. A method for treating a condition characterized by dysfunction in protein homeostasis in a patient in need thereof is provided which comprises administering to the patient a proteostasis regulator in an amount effective to improve or restore protein homeostasis, and to reduce or eliminate the condition in the patient or to prevent its occurrence or recurrence. The condition can be a loss of function disorder such as a lysosomal storage disease, or a gain of function disorder such as an aging associated disease. </p>
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In vivo unnatural amino acid expression in the methylotrophic yeast pichia pastoris (Fri, 07 Aug 2009)
<p id="p-0001-en" num="0000">The invention provides orthogonal translation systems for the production of polypeptides comprising unnatural amino acids in methylotrophic yeast such as <i>Pichia pastoris</i>. Methods for producing polypeptides comprising unnatural amino acids in methylotrophic yeast such as <i>Pichia pastoris </i>are also provided.</p>
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OXAZOLE-PYRROLE-PIPERAZINE ALPHA-HELIX MIMETIC (Fri, 07 Aug 2009)
<p id="p-0001-en" num="0000">Amphiphilic α-helix mimetics are provided. These compounds are constructed using an oxazole-pyrrole-piperazine (OPP) scaffold. The amphiphilic α-helix mimetics are also employable for making libraries and for treating diseases or conditions effected by the inhibition or disruption of interactions with the alpha helix of a protein.</p>
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OXAZOLE-PYRROLE-PIPERAZINE α-HELIX MIMETIC (Fri, 07 Aug 2009)
Amphiphilic α-helix mimetics of Formula I are provided. These compounds are constructed using an oxazole-pyrrole-piperazine (OPP) scaffold. The amphiphilic α-helix mimetics are also employable for making libraries and for treating diseases or conditions effected by the inhibition or disruption of interactions with the alpha helix of a protein.
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HUMAN AMINOACYL-tRNA SYNTHETASE POLYPETIDES USEFUL FOR THE REGULATION OF ANGIOGENESIS (Tue, 04 Aug 2009)

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COMPOSITIONS AND METHODS FOR COUPLING A PLURALITY OF COMPOUNDS TO A SCAFFOLD (Fri, 17 Jul 2009)
<p id="p-0001-en" num="0000">Compositions and methods are provided for coupling a plurality of compounds to a scaffold. Compositions and methods are further provided for catalyzing a reaction between at least one terminal alkyne moiety and at least one azide moiety, wherein one moiety is attached to the compound and the other moiety is attached to the scaffold, forming at least one triazole thereby.</p>
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Adding photoregulated amino acids to the genetic code (Fri, 17 Jul 2009)
<p id="p-0001-en" num="0000">Compositions and methods of producing components of protein biosynthetic machinery that include orthogonal leucyl-tRNAs, orthogonal leucyl-aminoacyl-tRNA synthetases, and orthogonal pairs of leucyl-tRNAs/synthetases, which incorporate photoregulated amino acids, OMe-L-tyrosine, α-aminocaprylic acid, or o-nitrobenzyl cysteine into proteins are proteins are provided in response to an amber selector codon. Methods for identifying these orthogonal pairs are also provided along with methods of producing proteins with a photoregulated amino acid, Ome-L-tyrosine, α-aminocaprylic acid, or o-nitrobenzyl cysteine using these orthogonal pairs.</p>
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Method for making amphiphilic dendrimers (Fri, 17 Jul 2009)
<p id="p-0001-en" num="0000">A series of AB-type amphiphilic dendritic polyesters have been prepared divergently, in which two hybrids were coupled via the copper(1)-catalyzed triazole formation.</p>
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Inhibiting tumor cell invasion, metastasis and angiogenesis (Fri, 10 Jul 2009)
<p id="p-0001" num="0000">The present invention relates to new compositions and methods useful for preventing, treating and diagnosing metastatic and/or invasive cancer and undesirable angiogenesis. For example, the invention relates to inhibitors of proteases that are specifically expressed in tumors, prodrugs activated in the tumor microenvironment and methods for using those inhibitors and prodrugs to inhibit angiogenesis and tumor cell invasion.</p>
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ANILIDES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 26 Jun 2009)
Compounds useful as Rho kinase inhibitors of formula (I): wherein variable are as defined herein are provided. Methods of treatment of malconditions mediated by Rho kinase, and methods of preparation of the compounds, are also provided.
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BENZOPYRANS AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 26 Jun 2009)
Compounds useful as Rho kinase inhibitors of formula (I) wherein the variables are as defined herein are provided. Methods of treatment of malconditions mediated by Rho kinase, and methods of preparation of the compounds, are also provided.
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BENZIMIDAZOLES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 26 Jun 2009)
Compounds useful as Rho kinase inhibitors according to formula IA or IB: wherein A, B, D, E, R1, R2 and Ar1 are as defined herein, and any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof, pharmaceutical compositions, methods of treatment, and synthetic methods are provided.
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BENZIMIDAZOLES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 26 Jun 2009)
Compounds useful as Rho kinase inhibitors according to formula IA or IB: wherein A, B, D, E, R1, R2 and Ar1 are as defined herein, and any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof, pharmaceutical compositions, methods of treatment, and synthetic methods are provided. </p>
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ANILIDES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 26 Jun 2009)
Compounds useful as Rho kinase inhibitors of formula (I): wherein variable are as defined herein are provided. Methods of treatment of malconditions mediated by Rho kinase, and methods of preparation of the compounds, are also provided. </p>
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BENZOPYRANS AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 26 Jun 2009)
Compounds useful as Rho kinase inhibitors of formula (I) wherein the variables are as defined herein are provided. Methods of treatment of malconditions mediated by Rho kinase, and methods of preparation of the compounds, are also provided. </p>
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IN VIVO UNNATURAL AMINO ACID EXPRESSION IN THE METHYLOTROPHIC YEAST PICHIA PASTORIS (Fri, 19 Jun 2009)
The invention provides orthogonal translation systems for the production of polypeptides comprising unnatural amino acids in methylotrophic yeast such as Pichia pastoris. Methods for producing polypeptides comprising unnatural amino acids in methylotrophic yeast such as Pichia pastoris are also provided.
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IN VIVO UNNATURAL AMINO ACID EXPRESSION IN THE METHYLOTROPHIC YEAST PICHIA PASTORIS (Fri, 19 Jun 2009)
The invention provides orthogonal translation systems for the production of polypeptides comprising unnatural amino acids in methylotrophic yeast such as Pichia pastoris. Methods for producing polypeptides comprising unnatural amino acids in methylotrophic yeast such as Pichia pastoris are also provided. </p>
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GENETICALLY ENCODED BORONATE AMINO ACID (Fri, 12 Jun 2009)
<p id="p-0001-en" num="0000">Provided are compositions comprising an aminoacyl tRNA synthetase that selectively recognizes a boronic amino acid. Methods of incorporating a boronic amino acid into a target polypeptides and target polypeptides produced by the methods are also provided. Methods of producing a protein, which methods comprise site-specifically encoding a boronic amino acid residue into a mutant protein and selectively converting the boronic amino acid residue into a natural amino acid residue are provided. Also provided are compositions comprising a solid phase matrix covalently bound to a polypeptide through a boronic amino acid residue. In addition, compositions comprising a purified population of polypeptide molecules that each comprise a borono amino acid at a selected site are provided.</p>
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DIRECTED EVOLUTION USING PROTEINS COMPRISING UNNATURAL AMINO ACIDS (Fri, 15 May 2009)
The invention provides methods and compositions for screening polypeptide libraries that include variants comprising unnatural amino acids. In addition, the invention provides vector packaging systems and methods for packaging a nucleic acid in a vector. Compositions of vectors produced by the methods and systems are also provided
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DIRECTED EVOLUTION USING PROTEINS COMPRISING UNNATURAL AMINO ACIDS (Fri, 15 May 2009)
The invention provides methods and compositions for screening polypeptide libraries that include variants comprising un-natural amino acids. In addition, the invention provides vector pack-aging systems and methods for packaging a nucleic acid in a vector. Compositions of vectors produced by the methods and systems are also provided </p>
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Small Molecule Mimetics of Erythropoietin (Fri, 08 May 2009)
<p id="p-0001-en" num="0000">The invention features computer-assisted methods for identifying molecules which will bind to the EPO receptor and act as an erythropoietin (EPO) mimetic. Preferred EPO mimetics identified using the method of the invention act as agonists of the EPO receptor in one or more in vitro or in vivo biological assays of EPO activity.</p>
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A GENETICALLY ENCODED BORONATE AMINO ACID (Fri, 08 May 2009)
Provided are compositions comprising an aminoacyl tRNA synthetase that selectively recognizes a boronic amino acid. Methods of incorporating a boronic amino acid into a target polypeptides and target polypeptides produced by the methods are also provided. Methods of producing a protein, which methods comprise site-specifically encoding a boronic amino acid residue into a mutant protein and selectively converting the boronic amino acid residue into a natural amino acid residue are provided. Also provided are compositions comprising a solid phase matrix covalently bound to a polypeptide through a boronic amino acid residue. In addition, compositions comprising a purified population of polypeptide molecules that each comprise a borono amino acid at a selected site are provided.
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METHODS AND COMPOSTIONS FOR OBTAINING HIGH-RESOLUTION CRYSTALS OF MEMBRANE PROTEINS (Fri, 01 May 2009)
The invention describes compositions and method useful for the crystallization of membrane proteins.
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CHOLESTEROL CONSENSUS MOTIF OF MEMBRANE PROTEINS (Fri, 01 May 2009)
The invention provides the structure of a human β2-adrenergic receptor, a cholesterol consensus motif, and methods of identifying modulators of G-protein coupled receptors (GPCRs). Methods of using the modulators of the receptor, GPCRs, and the cholesterol consensus motif are also provided.
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GENETIC INCORPORATION OF 3-AMINOTYROSINE INTO REDUCTASES (Fri, 01 May 2009)
This invention provides reductase proteins that comprise NH2Y unnatural amino acid residues, systems of orthogonal elements for incorporating NH2Y into reductases and methods of using NH2Y amino acid residues in reductases as molecular probes for probing reductases function, structure and activity.
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GENETIC INCORPORATION OF 3-AMINOTYROSINE INTO REDUCTASES (Fri, 01 May 2009)
This invention provides reductase proteins that comprise NH2Y unnatural amino acid residues, systems of orthogonal elements for incorporating NH2Y into reductases and methods of using NH2Y amino acid residues in reductases as molecular probes for probing reductases function, structure and activity. </p>
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METHODS AND COMPOSITIONS FOR OBTAINING HIGH-RESOLUTION CRYSTALS OF MEMBRANE PROTEINS (Fri, 01 May 2009)
<br/><br/>The invention describes compositions and method useful for the crystallization <br/>of membrane proteins.<br/></p>
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METHODS AND COMPOSITIONS FOR THE SITE-SELECTIVE INCORPORATION OF FLUORINATED AMINO ACIDS INTO POLYPEPTIDES (Fri, 17 Apr 2009)
Compositions including orthogonal aminoacyl-tRNA synthetases (O-RS) that preferentially aminoacylate an orthogonal tRNA (O-tRNA) with trifluoromethoxyphenylalanine are provided. Nucleic acids encoding these aminoacyl-tRNA synthetases are also provided.
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Site-specific labeling of proteins for NMR studies (Fri, 27 Mar 2009)
<p id="p-0001-en" num="0000">Methods of producing and/or analyzing spectroscopically labeled proteins, e.g., proteins site-specifically labeled with NMR active isotopes, spin-labels, chelators for paramagnetic metals, and the like, are provided. The labeled proteins are produced in translation systems including orthogonal aminoacyl tRNA synthetase/tRNA pairs. Methods for assigning NMR resonances, e.g., methods using isotopically labeled proteins, are also provided.</p>
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LIGANDS FOR COPPER-CATALYZED AZIDE-ALKYNE CYCLOADDITION REACTIONS (Fri, 27 Mar 2009)
Ligands useful for promoting copper-catalyzed azide-alkyne cycloaddition reactions comprise a compound represented by structural Formula (I) as described in the specification, wherein in Formula (I) Z1 is a nitrogen-containing heterocyclic group or a group represented by the formula : Y1-(CH2)c-Y2-(CH2)d-Y3-CH2-N(CH2Z4)(CH2Z5), where Y1 is -E1-C(O)O-, -E1-C(O)NH-, -E1-, or a covalent bond; Y2 is a covalent bond, -CH=CH-, or a 1,4-(1,2,3-triazolyl) group; Y3 is -OC(O)-E2-, -NHC(O)-E2-, -E2-, or a covalent bond; each of E1 and E2 is a benzimidazolyl group attached at the 1 and 2 positions; each of c and d is independently 1, 2, 3, 4, or 5; each of Z2, Z3, Z4 and Z5 is a nitrogen-containing heterocyclic group including a substituent X1 and optionally including a substituent (CH2)n-R1, and Y1, Y2, Y3, X1, R1, c, d and n are each as defined in the specification.
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METHODS FOR PRODUCING ANTI-GLYCAN ANTIBODIES, VACCINES AND METHODS FOR TREATING CANCER OR INFECTIOUS DISEASE (Fri, 20 Mar 2009)
The invention provides vaccines that comprise protein nanoparticles at least some of which are covalently bound to glycan-containing molecules. The invention also provides methods for producing anti-glycan antibodies in a vertebrate subject. The invention further provides methods for treating cancer or infectious diseases.
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ENZYME REGULATING ETHER LIPID SIGNALING PATHWAYS (Fri, 13 Mar 2009)
<p id="p-0001-en" num="0000">A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.</p>
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In vivo incorporation of unnatural amino acids (Fri, 13 Mar 2009)
<p id="p-0001-en" num="0000">The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.</p>
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Pyridazine based alpha-helix mimetics (Fri, 13 Mar 2009)
<p id="p-0001-en" num="0000">The synthesis of new α-helix scaffolds mimicking i, i+3 or i+4, i+7 residues, was accomplished. The common pyridazine heterocycle originates from the easily available building block, 6. These scaffolds may be thought of as synthetic counterparts of amphiphilic α-helices having a “wet face” along one side and a hydrophobic face along the other side of the helix.</p>
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CLICK CHEMISTRY ROUTE TO TRIAZOLE DENDRIMERS (Fri, 13 Mar 2009)
<p id="p-0001-en" num="0000">The high efficiency and fidelity of click chemistry permits a large number of diverse dendrimers encompassing a wide variety of functionalities at the chain ends, repeat units, and/or core to be prepared. Almost quantitative yields were obtained during the synthesis. In some cases, filtration or solvent extraction was the only method required for purification. These features represent a significant advancement in dendrimer chemistry and demonstrate an evolving synergy between organic chemistry and functional materials.</p>
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SUBSTITUTED PYRIMIDINYL-AMINES AS PROTEIN KINASE INHIBITORS (Fri, 13 Mar 2009)
The present invention provides novel substituted pyrimidinyl-amines that are useful as inhibitors of protein kinases, especially c-Jun N-terminal kinases (JNK) and pharmaceutical compositions thereof and methods of using the same for treating conditions responsive to the inhibition of the JNK pathway.
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SUBSTITUTED PYRIMIDINYL-AMINES AS PROTEIN KINASE INHIBITORS (Fri, 13 Mar 2009)
The present invention provides novel substituted pyrimidinyl-amines that are useful as inhibitors of protein kinases, especially c-Jun N-terminal kinases (JNK) and pharmaceutical compositions thereof and methods of using the same for treating conditions responsive to the inhibition of the JNK pathway. </p>
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Methods and composition for the production of orthogonal tRNA-aminoacyl tRNA synthetase pairs (Fri, 27 Feb 2009)
<p id="p-0001" num="0000">This invention provides compositions and methods for generating components of protein biosynthetic machinery including orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, and orthogonal pairs of tRNAs/synthetases. Methods for identifying orthogonal pairs are also provided. These components can be used to incorporate unnatural amino acids into proteins in vivo.</p>
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Inhibitors of Transthyretin Amyloid Fibril Formation (Fri, 27 Feb 2009)
<p id="p-0001-en" num="0000">Bisaryloxime ethers and bisarylhydroazones are shown to be effective for inhibiting formation of amyloid fibrils of transthyretin.</p>
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PYRIDAZINE BASED ALPHA-HELIX MIMETICS (Fri, 27 Feb 2009)
The synthesis of new α-helix scaffolds mimicking i, i+3 or i+4, i+7 residues, was accomplished. The common pyridazine heterocycle originates from the easily available building block, 6. These scaffolds may be thought of as synthetic counterparts of amphiphilic α-helices having a 'wet face' along one side and a hydrophobic face along the other side of the helix.
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Modified α-galactosyl ceramides for staining and stimulating natural killer T cells (Fri, 20 Feb 2009)
<p id="p-0001" num="0000">Modified glycolipid compounds are provided. Also disclosed are methods for activating an NKT cell, methods of stimulating an immune response in a subject, and methods suitable for labeling NKT cells.</p>
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GENOMIC MUTATION INHIBITORS THAT INHIBIT Y FAMILY DNA POLYMERASES (Fri, 13 Feb 2009)
Modulators of error prone DNA polymerases are provided. Methods of inhibiting genomic mutation to inhibit the emergence of drug resistant target cells are also provided. Screening assays for identifying modulators of error prone DNA polymerases are provided.
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UPP AMPHIPHILIC ALPHA-HELIX MIMETICS (Fri, 13 Feb 2009)
Functionalized pyridazine derivatives having a low molecular weight and pharmaceutical compositions thereof are useful as alpha-helical mimetics for efficiently disrupting protein-protein interactions such as Bak/Bcl-XL, p53/HDM2, calmodulin/smooth muscle myosin light-chain kinase, and gp41 assembly and for treating conditions and/or disorders mediated by disruption of alpha-helix-binding receptors and proteins.
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Crystal of a cytochrome-ligand complex and methods of use (Fri, 23 Jan 2009)
<p id="p-0001" num="0000">The teachings relates to the three-dimensional structure of a crystal of a cytochrome protein complexed with a ligand. The three-dimensional structure of four cytochrome P450 2A6-ligand complexes are disclosed. Cytochrome P450 2A6-ligand crystal structures, wherein the ligand is an inhibitor molecule, are useful for providing structural information that may be integrated into drug screening and drug design processes. Thus, the teachings also relate to methods for utilizing a crystal structure of a cytochrome P450 2A6-ligand complex for identifying, designing, selecting, or testing inhibitors of the cytochrome protein. Such inhibitors are useful as therapeutics for the treatment or modulation of i) diseases; ii) disease symptoms; or iii) the effect of other physiological events mediated by the cytochrome.</p>
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Oligonucleotide compound and method for treating nidovirus infections (Fri, 09 Jan 2009)
<p id="p-0001" num="0000">A method and oligonucleotide compound for inhibiting replication of a nidovirus in virus-infected animal cells are disclosed. The compound (i) has a nuclease-resistant backbone, (ii) is capable of uptake by the infected cells, (iii) contains between 8-25 nucleotide bases, and (iv) has a sequence capable of disrupting base pairing between the transcriptional regulatory sequences in the 5′ leader region of the positive-strand viral genome and negative-strand 3′ subgenomic region. In practicing the method, infected cells are exposed to the compound in an amount effective to inhibit viral replication.</p>
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Expression system for synthetic zinc finger proteins and methods of using the same (Fri, 02 Jan 2009)
<p id="p-0001-en" num="0000">The invention relates to the field of plant and agricultural technology. More specifically, the invention relates to the use of zinc finger proteins and fusions of said proteins to regulate gene expression and metabolic pathways in plants.</p>
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Polymeric materials via click chemistry (Fri, 19 Dec 2008)
<p id="p-0001" num="0000">Adhesive polymers are formed when polyvalent azides and alkynes are assembled into crosslinked polymer networks by copper-catalyzed 1,3-dipolar cycloaddition. The condensation polymerization is efficiently promoted by Cu ions either leached from the metal surface or added to the monomer mixture, and strong interactions with metal surfaces are provided by the multiple triazole binding elements produced. The adhesive polymers may be formed either as adhesive polymer coatings or as adhesive polymer cement.</p>
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TRICYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 12 Dec 2008)
A series of substituted oxazole compounds having an alpha keto side chain at the 2 position and an aromatic, heteroaromatic or heterocycle substituent at the 5 position are disclosed. These compounds exhibit inhibition of fatty acid amid hydrolase and are useful for treatment of malconditions involving that enzyme.
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INHIBITORS OF PROTEIN KINASES (Fri, 12 Dec 2008)
The invention provides inhibitors of protein kinases, such as an Src kinase, enzymes which has been implicated in processes such as cell migration, proliferation, and survival. The inhibitors include 2,5-disubstituted derivatives of thiazole wherein the substituents are as defined. The invention also provides a method of using the inhibitors in treatment of cancer, and a method of preparation of the inhibitors by a palladium-catalyzed coupling reaction.
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TRICYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 12 Dec 2008)
A series of substituted oxazole compounds having an alpha keto side chain at the 2 position and an aromatic, heteroaromatic or heterocycle substituent at the 5 position are disclosed. These compounds exhibit inhibition of fatty acid amid hydrolase and are useful for treatment of malconditions involving that enzyme.</p>
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Antitoxin and vaccine platform based on nodavirus VLPs (Fri, 05 Dec 2008)
<p id="p-0001" num="0000">Antitoxin and vaccine compositions based on nodavirus VLPs are provided. Anthrax antitoxin and vaccine compositions are provided. Methods of treating toxins with VLP-based antitoxins are provided. Methods of raising an immune response with immunogen decorated VLPs are provided.</p>
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TETRACYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 05 Dec 2008)
Certain tetracyclic compounds are described, which may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).
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TETRACYCLIC INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 05 Dec 2008)
Certain tetracyclic compounds are described, which may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).</p>
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Chemical synthesis of a highly potent epothilone (Fri, 28 Nov 2008)
<p id="p-0001" num="0000">A highly active synthetic epothilone compound whose activity exceeds that of either epothilone EpoA or EpoB when assayed as a cytotoxic agent against a cancer cell line is disclosed as is a pharmaceutical composition containing the synthetic epothilone.</p>
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Compounds and compositions as protein kinase inhibitors (Fri, 21 Nov 2008)
<p id="p-0001-en" num="0000">The invention provides a novel class of compounds of formula I, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the AbI, Bcr-AbI, Aurora-A, SGK, Tie-2, Trk-B, FGFR3, c-kit, b-RAF, c-RAF, DYRK2, Fms, Fyn and PDGFRalpha and PDGFR&;bgr; kinases.</p> <p id="p-0002-en" num="0000"> <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001" he="21.59mm" wi="59.52mm" file="US07589101-20090915-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> </p>
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Bacterial Glycolipid Activation of Cd1d-Restricted Nkt Cells (Fri, 14 Nov 2008)
<p id="p-0001-en" num="0000">Disclosed are methods for activating an NKT cell, methods of stimulating an immune response in a subject, methods of improving vaccine efficacy, and methods of treating an infection. Also disclosed are methods of promoting tumor rejection, treating cancer, modulating autoimmunity and inhibiting allergen-induced hypersensitivity in subjects. The methods include contacting an NKT cell with a bacterial glycolipid complexed with a CD1 molecule to activate the NKT cell. The bacterial glycolipid may be derived from a member of the Class Alphaproteobacteria.</p>
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PROTEINASE INHIBITORS AND USES THEREOF (Fri, 07 Nov 2008)
Compositions of inhibitors of proteases are identified. Methods of preventing and treating diseases associated with proteases comprise administering one or more inhibitors to a subject.
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CYSTEINE PROTEINASE INHIBITORS AND USES THEREOF (Fri, 07 Nov 2008)
Compounds described herein, derivatives and analogs thereof are potent proteases inhibitors. These compounds can be used to treat diseases such as those diseases caused by foreign organisms, e.g. fungi, bacteria, protozoa, and virus.
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ANTIVIRAL PEPTIDES (Fri, 07 Nov 2008)
The present application is directed to antiviral peptides, methods of using these peptides to prevent or inhibit infections by a human immunodeficiency virus or a virus from the Flaviviridae family, and pharmaceutical compositions and combinations, as well as articles of manufacture comprising these peptides.
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Compositions and Methods for Delivery of Antitumor Agents (Fri, 31 Oct 2008)
<p id="p-0001-en" num="0000">Methods for treating a neoplastic disease with an antibody-cytotoxin conjugate molecule, methods of synthesizing an antibody-cytotoxin conjugate molecule are provided. Compounds that are useful as antibody-cytotoxin conjugate molecule or useful in the synthesis of these molecules are also provided.</p>
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Amino acid derivatives of indolinone based protein kinase inhibitors (Fri, 31 Oct 2008)
<p id="p-0001-en" num="0000">Amino acid derivatives of pyrrolyl-indolinones and their amide or ester derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.</p>
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In vivo incorporation of unnatural amino acids (Fri, 24 Oct 2008)
<p id="p-0001" num="0000">The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.</p>
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GLYCOLIPIDS AND ANALOGUES THEREOF AS ANTIGENS FOR NK T CELLS (Fri, 24 Oct 2008)
This invention relates to immunogenic compounds which serve as ligands for NKT (natural killer T) cells and to methods of use thereof in modulating immune responses.
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In vivo site-sepecific incorporation of N-acetyl-galactosamine amino acids in eubacteria (Fri, 03 Oct 2008)
<p id="p-0001-en" num="0000">Methods and compositions for making glycoproteins, both in vitro and in vivo, are provided. One method involves incorporating an unnatural amino acid having a N-acetylgalactosamine moiety into a protein; optionally, the N-acetylgalactosamine-containing unnatural amino acid can be further modified with additional sugars.</p>
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Subnanomolar Precipitator of Thiophilic Metals (Fri, 03 Oct 2008)
<p id="p-0001-en" num="0000">A fluorescent dye-doped crystalline assay is employed for selection and detection of thiophilic heavy metal ions. While comparable in analytical performance to known solution based methodologies, the formation of crystalline analytes provides for signal amplification, and consequently, a powerful platform whose analysis is directly amenable to high-throughput video capture systems. In a microcapillary format, this assay is capable of screening hundreds of samples per day for the presence of subnanomolar concentrations of Hg<sup>2+</sup> using a conventional fluorescence microscope.</p>
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Orthogonal translation components for the in vivo incorporation of unnatural amino acids (Fri, 26 Sep 2008)
<p id="p-0001" num="0000">The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate unnatural amino acids into proteins produced in eubacterial host cells such as <i>E. coli</i>, or in a eukaryotic host such as a yeast cell. The invention provides, for example but not limited to, novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing unnatural amino acids, and translation systems.</p>
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INHIBITORS OF FOCAL ADHESION KINASE (Fri, 26 Sep 2008)
The invention provides inhibitors of focal adhesion kinase, an enzyme involved in the attachment of the cytoskeleton of a cell to an extracellular matrix, which has been implicated in processes such as cell migration, cell proliferation, and cell survival. The inhibitors are derivatives of a 5-substituted 2,4-diaminopyridine wherein the substituents are as defined herein. The invention also provides a method of using the inhibitors in treatment of cancer, and methods of preparation of the inhibitors by use of coupling reactions.
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INHIBITORS OF FOCAL ADHESION KINASE (Fri, 26 Sep 2008)
The invention provides inhibitors of focal adhesion kinase, an enzyme involved in the attachment of the cytoskeleton of a cell to an extracellular matrix, which has been implicated in processes such as cell migration, cell proliferation, and cell survival. The inhibitors are derivatives of a 5-substituted 2,4-diaminopyridine wherein the substituents are as defined herein. The invention also provides a method of using the inhibitors in treatment of cancer, and methods of preparation of the inhibitors by use of coupling reactions.</p>
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Site specific incorporation of keto amino acids into proteins (Fri, 19 Sep 2008)
<p id="p-0001" num="0000">Compositions and methods of producing components of protein biosynthetic machinery that include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, and orthogonal pairs of tRNAs/synthetases, which incorporate keto amino acids into proteins are provided. Methods for identifying these orthogonal pairs are also provided along with methods of producing proteins with keto amino acids using these orthogonal pairs.</p>
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In vivo incorporation of unnatural amino acids (Fri, 19 Sep 2008)
<p id="p-0001" num="0000">The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.</p>
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Expanding the eukaryotic genetic code (Fri, 19 Sep 2008)
<p id="p-0001" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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In vivo incorporation of alkynyl amino acids into proteins in eubacteria (Fri, 12 Sep 2008)
<p id="p-0001-en" num="0000">The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate alkynyl amino acids such as para-propargyloxyphenylalanine into proteins produced in a eubacteria host such as <i>E. coli</i>. The invention provides novel orthoghonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing alkynyl amino acids, and cellular translation systems.</p>
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Glycoprotein synthesis (Fri, 05 Sep 2008)
<p id="p-0001-en" num="0000">Methods for making glycoproteins, both in vitro and in vivo, are provided. One method involves incorporating an unnatural amino acid into a protein and attaching one or more saccharide moieties to the unnatural amino acid. Another method involves incorporating an unnatural amino acid that includes a saccharide moiety into a protein. Proteins made by both methods can be further modified with additional sugars.</p>
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A NOVEL ANTITOXIN AND VACCINE PLATFORM BASED ON NODAVIRUS VLPS (Fri, 22 Aug 2008)
Antitoxin and vaccine compositions based on nodavirus VLPs are provided. Anthrax antitoxin and vaccine compositions are provided. Methods of treating toxins with VLP-based antitoxins are provided. Methods of raising an immune response with immunogen decorated VLPs are provided.
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PURINE COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS FOR THE TREATMENT OF PLASMODIUM RELATED DISEASES (Fri, 08 Aug 2008)
The invention provides a class of purine derivates, pharmaceutical compositions comprising such compounds and the use of such compounds to treat or prevent diseases or disorders associated with kinase activity, particularly malaria.
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COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS (Fri, 08 Aug 2008)
The invention provides a class of purine derivates, pharmaceutical compositions comprising such compounds and the use of such compounds to treat or prevent diseases or disorders associated with kinase activity, particularly malaria.</p>
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Synthesis of proteins by native chemical ligation (Wed, 06 Aug 2008)
<p id="p-0001-en" num="0000">Proteins of moderate size having native peptide backbones are produced by a method of native chemical ligation. Native chemical ligation employs a chemoselective reaction of two unprotected peptide segments to produce a transient thioester-linked intermediate. The transient thioester-linked intermediate then spontaneously undergoes a rearrangement to provide the full length ligation product having a native peptide bond at the ligation site. Full length ligation products are chemically identical to proteins produced by cell free synthesis. Full length ligation products may be refolded and/or oxidized, as allowed, to form native disulfide-containing protein molecules. The technique of native chemical ligation is employable for chemically synthesizing full length proteins.</p>
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Expanding the eukaryotic genetic code (Fri, 25 Jul 2008)
<p id="p-0001-en" num="0000">This invention provides compositions and methods for producing translational components that expand the number of genetically encoded amino acids in eukaryotic cells. The components include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, orthogonal pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.</p>
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Site specific incorporation of keto amino acids into proteins (Fri, 25 Jul 2008)
<p id="p-0001-en" num="0000">Compositions and methods of producing components of protein biosynthetic machinery that include orthogonal tRNAs, orthogonal aminoacyl-tRNA synthetases, and orthogonal pairs of tRNAs/synthetases, which incorporate keto amino acids into proteins are provided. Methods for identifying these orthogonal pairs are also provided along with methods of producing proteins with keto amino acids using these orthogonal pairs.</p>
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Site-Specific Labeling of Proteins for Nmr Studies (Fri, 18 Jul 2008)
<p id="p-0001-en" num="0000">Methods of producing and/or analyzing spectroscopically labeled proteins, e.g., proteins site-specifically labeled with NMR active isotopes, spin-labels, chelators for paramagnetic metals, and the like, are provided. The labeled proteins are produced in translation systems including orthogonal aminoacyl tRNA synthetase/tRNA pairs. Methods for assigning NMR resonances, e.g., methods using isotopically labeled proteins, are also provided.</p>
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In vivo incorporation of unnatural amino acids (Fri, 11 Jul 2008)
<p id="p-0001" num="0000">The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.</p>
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In vivo incorporation of unnatural amino acids (Fri, 11 Jul 2008)
<p id="p-0001" num="0000">The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.</p>
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Compositions and methods for treatment of autoimmune and related diseases (Fri, 27 Jun 2008)
<p id="p-0001-en" num="0000">Compositions and methods are provided for treatment of autoimmune and other related diseases. 3d, a point mutation of the protein uncoordinated-93b (unc-93B), unc-93A, unc-93B, and unc-93C, polypeptides, nucleic acids encoding them and methods for making and using them, for example, to produce transgenic non-human animals.</p>
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METHODS FOR TREATMENT OF INFLAMMATORY DISEASE AND CHLAMYDIA INFECTIOUS DISEASE (Fri, 30 May 2008)
<p id="p-0001-en" num="0000">Methods are provided for treatment of inflammation or inflammatory disease. Methods are further provided for treatment of <i>Chlamydia </i>infection or persistent <i>Chlamydia </i>infection.</p>
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AN ENZYME REGULATING ETHER LIPID SIGNALING PATHWAYS (Fri, 30 May 2008)
A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.
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AN ENZYME REGULATING ETHER LIPID SIGNALING PATHWAYS (Fri, 30 May 2008)
A multidimensional profiling strategy that combines activity-based proteomics and metabolomics was used to determine that an active protein, which is a previously uncharacterized enzyme highly elevated in aggressive cancer cells, serves as a central node in an ether lipid signaling network that bridges platelet-activating factor and the lysophospholipids. Biochemical studies confirmed that the active protein regulates this pathway by hydrolyzing the metabolic intermediate 2-acetyl monoalkylglycerol. Inactivation of the active protein disrupted ether lipid metabolism in cancer cells and impaired cell migration and tumor growth in vivo.</p>
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BACTERIAL GLYCOLIPID ACTIVATION OF CD1D-RESTRICTED NKT CELLS (Thu, 01 May 2008)
</p> <p>of improving vaccine efficacy, and methods of treating an infection. Also disclosed are methods of promoting tumor rejection, treating cancer, modulating autoimmunity and inhibiting allergen-induced hypersensitivity in subjects. The methods include contacting o an NKT ccll with a bacterial glycolipid complcxcd with a CDI molecule to activate the NKT cell. The bacterial glycolipid may be derived from a member of the ("lass Alphaproieobacieria.
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Oxadiazole ketone inhibitors of fatty acid amide hydrolase (Fri, 25 Apr 2008)
<p id="p-0001-en" num="0000">Certain oxadiazole ketone compounds are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as MS). </p>
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Labeled peptides, and processes and intermediates useful for their preparation (Wed, 02 Apr 2008)
<p id="p-0001-en" num="0000">The invention provides intermediates and methods that allow for site-specific modification of peptides after synthesis. Accordingly, functional molecules can be selectively linked to a peptide to provide a peptide conjugate having altered biological, chemical, or physical properties. For example, functional molecules (e.g. biophysical probes, peptides, polynucleotides, and therapeutic agents) can be linked to a peptide to provide a peptide conjugate having differing and useful properties. The invention also provides a compound of formula (III):</p> <p id="p-0002-en" num="0000"> <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001" he="10.92mm" wi="26.67mm" file="US07351797-20080401-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> wherein: <br/> R<sup>6 </sup>is a peptide; <br/> X is a direct bond or a linking group; <br/> R<sup>7 </sup>is hydrogen, (C<sub>1</sub>-C<sub>6</sub>)alkyl, an amino protecting group, or a radical comprising one or more aminooxy groups; <br/> Y is a direct bond or a linking group; and <br/> D is a functional molecule. </p>
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METHODS FOR TREATMENT OF INFLAMMATORY DISEASE AND CHLAMYDIA INFECTIOUS DISEASE (Fri, 28 Mar 2008)
Methods are provided for treatment of inflammation or inflammatory disease. Methods are further provided for treatment of Chlamydia infection or persistent Chlamydia infection.
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Crystal of a Receptor-Ligand Complex and methods of use (Fri, 14 Mar 2008)
<p id="p-0001-en" num="0000">The invention relates to the three-dimensional structure of a crystal of an EphB4 receptor complexed with a ligand. The three-dimensional structure of a Receptor-Ligand Complex is disclosed. The receptor-ligand crystal structure, wherein the ligand is an inhibitor molecule, is useful for providing structural information that may be integrated into drug screening and drug design processes. Thus, the invention also relates to methods for utilizing the crystal structure of the Receptor-Ligand Complex for identifying, designing, selecting, or testing inhibitors of the EphB4 receptor protein, such inhibitors being useful as therapeutics for the treatment or modulation of i) diseases; ii) disease symptoms; or iii) the effect of other physiological events mediated by the receptor. </p>
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SUBSTITUTED OXAZOLE KETONE MODULATORS OF FATTY ACID AMIDE HYDROLASE (Fri, 14 Mar 2008)
Certain oxazole ketone compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).
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SUBSTITUTED OXAZOLE KETONE MODULATORS OF FATTY ACID AMIDE HYDROLASE (Fri, 14 Mar 2008)
Certain oxazole ketone compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity. Thus, the compounds may be administered to treat, e.g., anxiety, pain, inflammation, sleep disorders, eating disorders, or movement disorders (such as multiple sclerosis).</p>
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SULFHYDRYL-REACTIVE, WATER SOLUBLE DYES (Fri, 07 Mar 2008)
The invention relates to novel dye compounds and to methods of joining compounds, such as the dye compounds of the invention, to ulfhydryl-containing compounds.
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Genetically encoded fluorescent coumarin amino acids (Fri, 22 Feb 2008)
<p id="p-0001-en" num="0000">The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate the coumarin unnatural amino acid L-(7-hydroxycoumarin-4-yl) ethylglycine into proteins produced in eubacterial host cells such as <i>E. coli</i>. The invention provides, for example but not limited to, novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing the unnatural amino acid L-(7-hydroxycoumarin-4-yl)ethylglycine and related translation systems.</p>
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USE OF RETRO-ALDOL REACTION TO GENERATE REACTIVE VINYL KETONE FOR ATTACHMENT TO ANITIBODY MOLECULES BY MICHAEL ADDITION REACTION FOR USE IN IMMUNOSTAINING AND IMMUNOTARGETING (Fri, 11 Jan 2008)
The present invention is directed to methods for formation of a chemically programmed antibody comprising the steps of: (1) reacting a conjugate comprising a signal module covalently linked to a proadapter with a catalytic moiety selected from the group consisting of a catalytic antibody and a Fab fragment of a catalytic antibody, wherein the proadapter includes therein a precursor to a reactive moiety activated to a reactive moiety by a reaction catalyzed by the catalytic moiety; and (2) crosslinking the reactive moiety to a side chain of an amino acid residue in the active site of the catalytic moiety to produce the chemically programmed antibody. The invention also encompasses chemically programmed antibodies formed by these methods, methods for their use, and pharmaceutical compositions, as well as proadaptors and conjugates including them. Chemically programmed antibodies are useful for the treatment of cancer, particularly in metastasis.
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CHIMERIC ZINC FINGER RECOMBINASES OPTIMIZED FOR CATALYSIS BY DIRECTED EVOLUTION (Fri, 11 Jan 2008)
The present invention is directed to chimeric recombinases comprising a serine recombinase operativeiy iinked to a zinc finger nucleotide binding domain such that the chimeric recombinase protein catalyzes site-specific recombination at a DNA site specifically bound by the zinc finger nucleotide binding domain. The serine recombinase can be one of several naturally occurring serine recombinases. The invention also includes nucleic acids encoding the chimeric recombinases, vectors including the nucleic acids, host cells transformed or transfected with the vectors, methods of using the chimeric recombinases to carry out recombination, methods of using substrate-linked protein evolution to generate additional chimeric recombinases, methods of using the chimeric recombinases for gene therapy, and pharmaceutical compositions.
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CHIMERIC ZINC FINGER RECOMBINASES OPTIMIZED FOR CATALYSIS BY DIRECTED EVOLUTION (Fri, 11 Jan 2008)
The present invention is directed to chimeric recombinases comprising a serine recombinase operativeiy iinked to a zinc finger nucleotide binding domain such that the chimeric recombinase protein catalyzes site-specific recombination at a DNA site specifically bound by the zinc finger nucleotide binding domain. The serine recombinase can be one of several naturally occurring serine recombinases. The invention also includes nucleic acids encoding the chimeric recombinases, vectors including the nucleic acids, host cells transformed or transfected with the vectors, methods of using the chimeric recombinases to carry out recombination, methods of using substrate-linked protein evolution to generate additional chimeric recombinases, methods of using the chimeric recombinases for gene therapy, and pharmaceutical compositions.</p>
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GENETICALLY ENCODED FLUORESCENT COUMARIN AMINO ACIDS (Fri, 07 Dec 2007)
The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate the coumarin unnatural amino acid L-(7-hydroxycoumarin-4-yl) ethylglycine into proteins produced in eubacterial host cells such as E. coli. The invention provides, for example but not limited to, novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing the unnatural amino acid L-(7-hydroxycoumarin-4-yl) ethylglycine and related translation systems.
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GENETICALLY ENCODED FLUORESCENT COUMARIN AMINO ACIDS (Fri, 07 Dec 2007)
The invention relates to orthogonal pairs of tRNAs and aminoacyl-tRNA synthetases that can incorporate the coumarin unnatural amino acid L-(7-hydroxycoumarin-4-yl) ethylglycine into proteins produced in eubacterial host cells such as E. coli. The invention provides, for example but not limited to, novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing the unnatural amino acid L-(7-hydroxycoumarin-4-yl) ethylglycine and related translation systems.</p>
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Stabilized proteins with engineered disulfide bonds (Fri, 30 Nov 2007)
<p id="p-0001" num="0000">The present invention relates to methods of introducing one or more cysteine residues into a polypeptide which permit the stabilization of the polypeptide by formation of at least one bond, preferably a disulfide bond, between different domains of the polypeptide. The invention also relates to polypeptides containing such introduced cysteine residue(s), nucleic acids encoding such polypeptides and pharmaceutical compositions comprising such polypeptides or nucleic acids. The invention also relates to vectors, viral particles and host cells containing such nucleic acids, and methods of using them to produce the polypeptides of the invention. Exemplified polypeptides include plasma proteins, including hepatocyte growth factor activator and plasma hyaluronin binding protein, as well as blood coagulation factors, such as Factor VIII, Factor V, Factor XII and prothrombin.</p>
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Peptides That Bind To Atherosclerotic Lesions (Fri, 16 Nov 2007)
<p id="p-0001-en" num="0000">The present invention provides peptides that selectively bind to mammalian atherosclerotic lesions. The present invention also provides methods for in vivo identification of peptides capable of binding to biomolecules as well as methods for identifying the targets of such binding moieties. Methods to diagnose or treat pathologic conditions that involve atherosclerotic lesions are also provided by the invention that involve administering to a mammal a peptide attached to a reporter molecule or a therapeutic agent, respectively. </p>
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Compositions and methods for inducing cell dedifferentiation (Fri, 02 Nov 2007)
<p id="p-0001" num="0000">The present invention provides compounds, compositions and methods for dedifferentiating lineage committed mammalian cells into stem cells. The present invention also provides methods of inducing dedifferentiation of lineage committed mammalian cells into stem cells, which can be further differentiated into various lineage committed cells. Methods of identifying additional compounds useful for inducing dedifferentiation of lineage committed cells into stem cells are also provided.</p>
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COMPOSITIONS AND METHODS FOR TREATING GRAM POSITIVE BACTERIAL INFECTION IN A MAMMALIAN SUBJECT (Fri, 26 Oct 2007)
Compositions and methods are provided for treating Gram positive bacterial infection in a mammalian subject. Compositions and methods are further provided for treating Gram positive bacterial skin infection in the mammalian subject. Compositions and methods are provided that comprise administering to the mammalian subject an effective amount of a compound that activates Scdl gene expression or activates Scdl gene product.
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COMPOSITIONS AND METHODS FOR TREATING GRAM POSITIVE BACTERIAL INFECTION IN A MAMMALIAN SUBJECT (Fri, 26 Oct 2007)
Compositions and methods are provided for treating Gram positive bacterial infection in a mammalian subject. Compositions and methods are further provided for treating Gram positive bacterial skin infection in the mammalian subject. Compositions and methods are provided that comprise administering to the mammalian subject an effective amount of a compound that activates Scdl gene expression or activates Scdl gene product. </p>
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MODIFIED -GALACTOSYL CERAMIDES FOR STAINING AND STIMULATING NATURAL KILLER T CELLS (Fri, 19 Oct 2007)
Modified glycolipid compounds are provided. Also disclosed are methods for activating an NKT cell, methods of stimulating an immune response in a subject, and methods suitable for labeling NKT cells.
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MODIFIED .ALPHA.-GALACTOSYL CERAMIDES FOR STAINING AND STIMULATING NATURAL KILLER T CELLS (Fri, 19 Oct 2007)
Modified glycolipid compounds are provided. Also disclosed are methods for activating an NKT cell, methods of stimulating an immune response in a subject, and methods suitable for labeling NKT cells.</p>
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Glycolipids and analogues thereof as antigens for NKT cells (Fri, 12 Oct 2007)
<p id="p-0001" num="0000">This invention relates to immunogenic compounds which serve as ligands for NKT (natural killer T) cells and to methods of use thereof in modulating immune responses.</p>
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METHOD OF PREPARING GLYCOPEPTIDES (Fri, 05 Oct 2007)
A method is provided for the synthesis of glycopeptides using a sugar assisted ligation strategy, wherein an N-terminal peptide portion in the form of a thioester is coupled with a C-terminal peptide portion bearing a carbohydrate moiety comprising a thiol group.
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METHODS OF SCREENING FOR ANTITUMOR AGENTS (Fri, 28 Sep 2007)
<p id="p-0001-en" num="0000">This invention provides cellular regulators of antitumor agent apratoxin A. The invention also provides methods for identifying novel antitumor compounds using these cellular regulators of apratoxin A. The methods comprise first screening test agents for modulators of a cellular regulator of apratoxin A and then further screening the identified modulating agents for antitumor activities. The invention further provides methods and pharmaceutical compositions for treating tumors in a subject. </p>
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Labeled peptides, proteins and antibodies and processes and intermediates useful for their preparation (Fri, 21 Sep 2007)
<p id="p-0001-en" num="0000">The invention provides peptide synthons having protected functional groups for attachment of desired moieties (e.g. functional molecules or probes). Also provided are peptide conjugates prepared from such synthons, and synthon and conjugate preparation methods including procedures for identifying optimum probe attachment sites. Biosensors are provided having functional molecules that can locate and bind to specific biomolecules within living cells. Biosensors can detect chemical and physiological changes in those biomolecules as living cells are moving, metabolizing and reacting to its environment. Methods are included for detecting GTP activation of a Rho GTPase protein using polypeptide biosensors. When the biosensor binds GTP-activated Rho GTPase protein, an environmentally sensitive dye emits a signal of a different lifetime, intensity or wavelength than when not bound. New fluorophores whose fluorescence responds to environmental changes are also provided that have improved detection and attachment properties, and that can be used in living cells, or in vitro.</p>
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Histone deacetylase inhibitors as therapeutics for neurological diseases (Fri, 21 Sep 2007)
<p id="p-0001-en" num="0000"> The invention provides HDAC inhibitors that may be used as therapeutics for the treatment of a neurodegenerative or neuromuscular condition. The invention provides compounds of formula I: The invention also provides pharmaceutical compositions and articles of manufacture that include these compounds, as well as methods of treating and methods of preventing or delaying the onset of a neurodegenerative or neuromuscular condition. </p>
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Enzymatic nucleic acid molecules (Fri, 21 Sep 2007)
<p id="p-0001-en" num="0000">The present invention discloses nucleic acid enzymes and deoxyribonucleic acid enzymes capable of cleaving nucleic acid sequences or molecules, particularly RNA, in a site-specific manner, as well as compositions including same. Methods of making and using the disclosed enzymes and compositions are also disclosed.</p>
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SPECIFIC LABELING OF PROTEINS WITH ZINC FINGER TAGS AND USE OF ZINC-FINGER-TAGGED PROTEINS FOR ANALYSIS (Fri, 21 Sep 2007)
Fusion proteins including zinc finger tags that bind in a sequence-specific manner and a peptide, polypeptide, or protein can be prepared and expressed. Such fusion proteins can be used to generate protein arrays by binding the zinc finger tags to a DNA array. The fusion proteins can also be used to label cell surfaces with DNA tags. Fusion proteins according to the invention can be used to localize the peptide, polypeptide, or protein that is incorporated into the fusion protein by using a labeled DNA, such as a fluorescent DNA. The invention further includes vectors and host cells, as well as a method of analyzing double-stranded DNA.
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