Scripps - organic-reaction.com

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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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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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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Expanding the eukaryotic genetic code (Fri, 09 Nov 2012)
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.
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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)
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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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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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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Site specific incorporation of keto amino acids into proteins (Fri, 30 Dec 2011)
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.
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Chemically Programmed Vaccination (Fri, 23 Dec 2011)
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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STEM CELL CULTURES (Fri, 02 Dec 2011)
The present invention relates compounds for stabilizing cells and methods of their use.
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METHODS AND COMPOSITIONS RELATED TO TARGETING MONOACYLGLYCEROL LIPASE (Fri, 11 Nov 2011)
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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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)
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.
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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)
The present invention relates compounds for stabilizing cells and methods of their use.
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Expanding the eukaryotic genetic code (Fri, 09 Sep 2011)
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.
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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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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)
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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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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BENZOPYRANS AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 24 Jun 2011)
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. <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> 
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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)
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.
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Glycolipids and analogues thereof as antigens for NKT cells (Fri, 15 Apr 2011)
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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METHODS OF ACTIVATING NKT CELLS (Fri, 08 Apr 2011)
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.
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Protein arrays (Fri, 01 Apr 2011)
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.
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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)
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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Breaking Immunological Tolerance with a Genetically Encoded Unnatural Amino Acid (Fri, 04 Mar 2011)
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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BENZIMIDAZOLES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 04 Mar 2011)
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. <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> 
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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)
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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ANILIDES AND ANALOGS AS RHO KINASE INHIBITORS (Fri, 18 Feb 2011)
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. <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> 
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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)
The invention describes compositions and method useful for the crystallization of membrane proteins.
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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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Production of carrier-peptide conjugates using chemically reactive unnatural amino acids (Fri, 26 Nov 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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SUBSTITUTED PYRIMIDINYL-AMINES AS PROTEIN KINASE INHIBITORS (Fri, 26 Nov 2010)
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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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)
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.
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Enhanced Indolinone Based Protein Kinase Inhibitors (Fri, 22 Oct 2010)
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.
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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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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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Small Molecule Mimetics of Erythropoietin (Fri, 01 Oct 2010)
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.
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Tetracyclic inhibitors of fatty acid amide hydrolase (Fri, 01 Oct 2010)
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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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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COMPOUNDS THAT MAINTAIN PLURIPOTENCY OF EMBRYONIC STEM CELLS (Fri, 17 Sep 2010)
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. <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> 
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Tricyclic inhibitors of fatty acid amide hydrolase (Fri, 27 Aug 2010)
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.
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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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Expanding the eukaryotic genetic code (Fri, 25 Jun 2010)
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.
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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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6″-amino-6″-deoxygalactosylceramides (Fri, 04 Jun 2010)
This invention relates to galactosylceramide compounds.
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COMPOUNDS THAT INDUCE PANCREATIC BETA-CELL EXPANSION (Fri, 28 May 2010)
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.
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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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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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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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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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Pharmaceutically acceptable salt of 6-carboxy-2-(3,5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof (Fri, 14 May 2010)
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.
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Targeted delivery to legumain-expressing cells (Fri, 07 May 2010)
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.
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OXAZOLE-PYRIDAZINE-OXAZOLE ALPHA-HELIX MIMETIC (Fri, 07 May 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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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)
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.
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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)
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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PURINE COMPOUNDS AND COMPOSITIONS AS KINASE INHIBITORS FOR THE TREATMENT OF PLASMODIUM RELATED DISEASES (Fri, 05 Mar 2010)
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.
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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)
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.
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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)
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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Compositions and methods for inducing cell dedifferentiation (Fri, 29 Jan 2010)
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.
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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)
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.
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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)
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.
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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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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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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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ALKOXY INDOLINONE BASED PROTEIN KINASE INHIBITORS (Fri, 11 Dec 2009)
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.
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Method of using click chemistry to functionalize dendrimers (Fri, 11 Dec 2009)
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.
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NOVEL SCAFFOLDS FOR ALPHA-HELIX MIMICRY (Fri, 04 Dec 2009)
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.
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Genetically encoded fluorescent coumarin amino acids (Fri, 04 Dec 2009)
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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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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Methods to identify therapeutic agents (Fri, 06 Nov 2009)
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.
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INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 30 Oct 2009)
Potent inhibitors of fatty acid amide hydrolase (FAAH) are constructed having Ki's below 200 pM and activities 102-103 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 Δ8,9/Δ11,12 and/or oleyl Δ9,10 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).
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Breaking immunological tolerance with a genetically encoded unnatural amino acid (Fri, 23 Oct 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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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)
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.
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Methods and compositions for the production of orthogonal tRNA-aminoacyl-tRNA synthetase pairs (Fri, 11 Sep 2009)
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.
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Human aminoacyl-tRNA synthetase polypeptides useful for the regulation of angiogenesis (Fri, 11 Sep 2009)
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.
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Site specific incorporation of keto amino acids into proteins (Fri, 28 Aug 2009)
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.
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GENETIC INCORPORATION OF 3-AMINOTYROSINE INTO REDUCTASES (Fri, 21 Aug 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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COMPOUNDS AND COMPOSITIONS AS HEDGEHOG PATHWAY MODULATORS (Fri, 21 Aug 2009)
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.
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Compositions and methods for treating gram positive bacterial infection in a mammalian subject (Fri, 14 Aug 2009)
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.
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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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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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In vivo unnatural amino acid expression in the methylotrophic yeast pichia pastoris (Fri, 07 Aug 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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OXAZOLE-PYRROLE-PIPERAZINE ALPHA-HELIX MIMETIC (Fri, 07 Aug 2009)
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.
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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)
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.
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Adding photoregulated amino acids to the genetic code (Fri, 17 Jul 2009)
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.
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Method for making amphiphilic dendrimers (Fri, 17 Jul 2009)
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.
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Inhibiting tumor cell invasion, metastasis and angiogenesis (Fri, 10 Jul 2009)
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.
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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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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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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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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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GENETICALLY ENCODED BORONATE AMINO ACID (Fri, 12 Jun 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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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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Small Molecule Mimetics of Erythropoietin (Fri, 08 May 2009)
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.
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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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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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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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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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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)
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.
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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)
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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In vivo incorporation of unnatural amino acids (Fri, 13 Mar 2009)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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Pyridazine based alpha-helix mimetics (Fri, 13 Mar 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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CLICK CHEMISTRY ROUTE TO TRIAZOLE DENDRIMERS (Fri, 13 Mar 2009)
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.
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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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Inhibitors of Transthyretin Amyloid Fibril Formation (Fri, 27 Feb 2009)
Bisaryloxime ethers and bisarylhydroazones are shown to be effective for inhibiting formation of amyloid fibrils of transthyretin.
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Methods and composition for the production of orthogonal tRNA-aminoacyl tRNA synthetase pairs (Fri, 27 Feb 2009)
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.
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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)
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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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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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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Crystal of a cytochrome-ligand complex and methods of use (Fri, 23 Jan 2009)
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.
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Expression system for synthetic zinc finger proteins and methods of using the same (Fri, 02 Jan 2009)
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.
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Polymeric materials via click chemistry (Fri, 19 Dec 2008)
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.
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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.
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Antitoxin and vaccine platform based on nodavirus VLPs (Fri, 05 Dec 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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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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Chemical synthesis of a highly potent epothilone (Fri, 28 Nov 2008)
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.
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Compounds and compositions as protein kinase inhibitors (Fri, 21 Nov 2008)
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. <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> 
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Bacterial Glycolipid Activation of Cd1d-Restricted Nkt Cells (Fri, 14 Nov 2008)
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.
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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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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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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)
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.
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Amino acid derivatives of indolinone based protein kinase inhibitors (Fri, 31 Oct 2008)
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.
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In vivo incorporation of unnatural amino acids (Fri, 24 Oct 2008)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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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)
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.
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Subnanomolar Precipitator of Thiophilic Metals (Fri, 03 Oct 2008)
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 Hg2+ using a conventional fluorescence microscope.
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Orthogonal translation components for the in vivo incorporation of unnatural amino acids (Fri, 26 Sep 2008)
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 E. coli, 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.
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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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Site specific incorporation of keto amino acids into proteins (Fri, 19 Sep 2008)
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.
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In vivo incorporation of unnatural amino acids (Fri, 19 Sep 2008)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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Expanding the eukaryotic genetic code (Fri, 19 Sep 2008)
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.
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In vivo incorporation of alkynyl amino acids into proteins in eubacteria (Fri, 12 Sep 2008)
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 E. coli. 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.
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Glycoprotein synthesis (Fri, 05 Sep 2008)
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.
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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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Synthesis of proteins by native chemical ligation (Wed, 06 Aug 2008)
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.
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Site specific incorporation of keto amino acids into proteins (Fri, 25 Jul 2008)
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.
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Expanding the eukaryotic genetic code (Fri, 25 Jul 2008)
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.
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Site-Specific Labeling of Proteins for Nmr Studies (Fri, 18 Jul 2008)
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.
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In vivo incorporation of unnatural amino acids (Fri, 11 Jul 2008)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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In vivo incorporation of unnatural amino acids (Fri, 11 Jul 2008)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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Compositions and methods for treatment of autoimmune and related diseases (Fri, 27 Jun 2008)
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.
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METHODS FOR TREATMENT OF INFLAMMATORY DISEASE AND CHLAMYDIA INFECTIOUS DISEASE (Fri, 30 May 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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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.
>> read more

BACTERIAL GLYCOLIPID ACTIVATION OF CD1D-RESTRICTED NKT CELLS (Thu, 01 May 2008)
 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)
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). 
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Labeled peptides, and processes and intermediates useful for their preparation (Wed, 02 Apr 2008)
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): <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: R6 is a peptide; X is a direct bond or a linking group; R7 is hydrogen, (C1-C6)alkyl, an amino protecting group, or a radical comprising one or more aminooxy groups; Y is a direct bond or a linking group; and D is a functional molecule. 
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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)
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. 
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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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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)
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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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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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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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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Stabilized proteins with engineered disulfide bonds (Fri, 30 Nov 2007)
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.
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Peptides That Bind To Atherosclerotic Lesions (Fri, 16 Nov 2007)
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. 
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Compositions and methods for inducing cell dedifferentiation (Fri, 02 Nov 2007)
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.
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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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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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Glycolipids and analogues thereof as antigens for NKT cells (Fri, 12 Oct 2007)
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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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)
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. 
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Labeled peptides, proteins and antibodies and processes and intermediates useful for their preparation (Fri, 21 Sep 2007)
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.
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Histone deacetylase inhibitors as therapeutics for neurological diseases (Fri, 21 Sep 2007)
 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. 
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Enzymatic nucleic acid molecules (Fri, 21 Sep 2007)
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.
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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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Zinc finger binding domains for TNN (Fri, 14 Sep 2007)
Polypeptides that contain zinc finger-nucleotide binding regions that bind to nucleotide sequences of the formula TNN are provided. Compositions containing a plurality of polypeptides, isolated heptapeptides possessing specific binding activity, polynucleotides that encode such polypeptides and methods of regulating gene expression with such polypeptides, compositions and polynucleotides are also provided.
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Oxazole ketones as modulators of fatty acid amide hydrolase (Fri, 31 Aug 2007)
Certain oxazole 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).
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OXAZOLE KETONES AS MODULATORS OF FATTY ACID AMIDE HYDROLASE (Fri, 31 Aug 2007)
Certain oxazole 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).
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Glycoprotein synthesis (Fri, 10 Aug 2007)
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.
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Specific Labeling of Protein with Zinc Finger Tags and Use of Zinc-Finger-Tagged Proteins for Analysis (Fri, 03 Aug 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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Glycoprotein synthesis (Fri, 27 Jul 2007)
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.
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[PSI[CH2NH]PG4] glycopeptide antibiotic analogs (Fri, 27 Jul 2007)
[ψ[CH2NH]PG4] glycopeptide antibiotic analogs are reengineered forms of glycopeptides that exhibit antimicrobial activity against both wild type and glycopeptide antibiotic resistant strains of microorganisms. For example, [ψ[CH2NH]Tpg4] vancomycin aglycon is a reengineered form of vancomycin that exhibits antimicrobial activity (MIC=31 μg/mL) against both wild type and VanA resistant organism (E. faecalis BM4166). The VanA resistant organism achieves its resistance, upon glycopeptide antibiotic challenge, by remodeling its D-Ala-D-Ala peptidoglycan cell wall precursor to D-Ala-D-Lac. [ψ[CH2NH]PG4] glycopeptide antibiotic analogs have an altered glycopeptide backbone wherein the carbonyl of the fourth amino acid residue of the glycopeptide backbone has been replaced with a methylene. This alteration of the glycopeptide backbone imparts dual binding affinities for both D-Ala-D-Ala and D-Ala-D-Lac and dual antimicrobial activities for both wild type and resistant strains. For example, [ψ[CH2NH]Tpg4]vancomycin aglycon displays a antimicrobial potency that reflects its altered binding characteristics. 
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[ψ[CH2NH]PG4] GLYCOPEPTIDE ANTIBIOTIC ANALOGS (Fri, 27 Jul 2007)
[ψ[CH2NH]PG4] glycopeptide antibiotic analogs are reengineered forms of glycopeptides that exhibit antimicrobial activity against both wild type and glycopeptide antibiotic resistant strains of microorganisms. For example, [Ψ[CH2NH]Tpg4] vancomycin aglycon is a reengineered form of vancomycin that exhibits antimicrobial activity (MIC = 31 µg/mL) against both wild type and VanA resistant organism (E. faecalis BM4166). The VanA resistant organism achieves its resistance, upon glycopeptide antibiotic challenge, by remodeling its D-Ala-D-Ala peptidoglycan cell wall precursor to D-Ala-D-Lac. [ψ[CH2NH]PG4] glycopeptide antibiotic analogs have an altered glycopeptide backbone wherein the carbonyl of the fourth amino acid residue of the glycopeptide backbone has been replaced with a methylene. This alteration of the glycopeptide backbone imparts dual binding affinities for both D-Ala-D-Ala and D-Ala-D-Lac and dual antimicrobial activities for both wild type and resistant strains. For example, [Ψ[CH2NH]Tpg4]vancomycin aglycon displays a antimicrobial potency that reflects its altered binding characteristics.
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Expanding the eukaryotic genetic code (Fri, 20 Jul 2007)
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.
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PYRIMIDINONE DERIVATIVES AS PROTEIN KINASE INHIBITORS (Fri, 20 Jul 2007)
Pyrimidinone 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 inflammatory diseases and certain types of cancer.
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CRYSTAL OF A RECEPTOR-LIGAND COMPLEX AND METHODS OF USE (Fri, 20 Jul 2007)
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.
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ZINC FINGER DOMAINS SPECIFICALLY BINDING AGC (Fri, 20 Jul 2007)
Polypeptides that contain zinc finger-nucleoticle binding regions that bind to nucleotide sequences of the formula AGC are provided. Compositions containing a plurality of polypeptides, isolated heptapeptides possessing specific binding activity, polynucleotides that encode such polypeptides and methods of regulating gene expression with such polypeptides, compositions and polynucleotides are also provided.
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PIPERIDINE AMIDE DERIVATIVES AS PROTEIN KINASE INHIBITORS (Fri, 20 Jul 2007)
Piperidine 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 inflammatory diseases and certain types of cancer.
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AMINO ACID DERIVATIVES OF INDOLINONE BASED PROTEIN KINASE INHIBITORS (Fri, 20 Jul 2007)
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.
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Expanding the eukaryotic genetic code (Fri, 06 Jul 2007)
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.
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ZINC FINGER DOMAINS SPECIFICALLY BINDING AGC (Fri, 06 Jul 2007)
Polypeptides that contain zinc finger-nucleotide binding regions that bind to nucleotide sequences of the formula AGC are provided. Compositions containing a plurality of polypeptides, isolated heptapeptides possessing specific binding activity, polynucleotides that encode such polypeptides and methods of regulating gene expression with such polypeptides, compositions and polynucleotides are also provided. 
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INHIBITING TUMOUR CELL INVASION, METASTASIS AND ANGIOGENESIS THROUGH TARGETTING LEGUMAIN (Fri, 08 Jun 2007)
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.
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COMPOSITIONS AND METHODS FOR INDUCING NEURONAL DIFFERENTIATION (Fri, 08 Jun 2007)
The present invention provides compositions and methods for inducing neuronal cell differentiation.
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TRANS-3,5-DISUBSTITUTEDPYRROLIDINE: ORGANOCATALYST FOR ANTI-MANNICH REACTIONS (Fri, 01 Jun 2007)
A compound of Formula I is disclosed, in which R is a substituent containing a hydrogen bond-forming atom within three atoms from the ring carbon to which the substituent is bonded; X is CH2, 0, S or NR1, wherein Rl is a hydrocarbyl group or an amino-protecting group having one to about 18 carbon atoms; R2 is hydrido or a hydrocarbyl group containing one to about twelve carbon atoms,- and R3 is hydrido or methyl, but both R2 and R3 are not hydrido when X is CH2 (I) A molecule of Formula I and those in which R2 and R3 can both be hydrido (Formula X) functions as a catalyst in a Mannich reaction to asymmetrically form β- aminoaldehyde or β- aminoketone diastereomeric products having two chiral centers on adjacent carbon atoms and in which the anti- diastereomers are in excess over the syn- diastereomers. Methods for carrying out those syntheses are also disclosed.
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ZINC FINGER BINDING DOMAINS FOR TNN (Fri, 01 Jun 2007)
Polypeptides that contain zinc finger-nucleotide binding regions that bind to nucleotide sequences of the formula TNN are provided. Compositions containing a plurality of polypeptides, isolated heptapeptides possessing specific binding activity, polynucleotides that encode such polypeptides and methods of regulating gene expression with such polypeptides, compositions and polynucleotides are also provided.
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CHEMICAL SYNTHESIS OF A HIGHLY POTENT EPOTHILONE (Fri, 01 Jun 2007)
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.
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In vivo incorporation of unnatural amino acids (Fri, 25 May 2007)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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Synthetic zinc finger protein encoding sequences and methods of producing the same (Fri, 25 May 2007)
The invention relates to nucleic acids encoding synthetic zinc finger proteins for gene regulation in plants. The invention also relates to methods of producing synthetic zinc finger protein in host cells.
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HISTONE DEACETYLASE INHIBITORS AS THERAPEUTICS FOR NEUROLOGICAL DISEASES (Fri, 25 May 2007)
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.
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COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS (Fri, 11 May 2007)
The invention provides a novel class of compounds, 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-Abl, Aurora- A, AxI, BMX, CHK2, c-RAF, cSRC, Fes, FGFR3, Flt3, IKKα, IR, JNK2α2, Lck, Met, MKK6, MST2, p70S6K, PDGFRα, PKA, PKD2, ROCK-II, Ros, Rskl, SAPK2α, SAPK2β, SAPK3 SAPK4, Syk, Tie2 and TrkB kinases.
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VIRAL PEPTIDES AND THEIR USE TO INHIBIT VIRAL INFECTIONS AGAINST VIRUSES OF THE FLAVIRIDAE FAMILY (Fri, 13 Apr 2007)
The present application is directed to peptides that inhibit infection of a virus from the Flaviviridae family, methods of using these peptides to inhibit viral infections, and pharmaceutical compositions and combinations, as well as articles of manufacture comprising these peptides.
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RUTHENIUM-CATALYZED CYCLOADDITION OF ALKYNES AND ORGANIC AZIDES (Fri, 13 Apr 2007)
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.
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Methods for treating transthyretin amyloid diseases (Fri, 06 Apr 2007)
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.
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ALKOXY INDOLINONE BASED PROTEIN KINASE INHIBITORS (Fri, 06 Apr 2007)
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.
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Alkoxy indolinone based protein kinase inhibitors (Fri, 30 Mar 2007)
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.
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HIV GP120 CRYSTAL STRUCTURE AND ITS USE TO IDENTIFY IMMUNOGENS (Fri, 16 Mar 2007)
The present disclosure relates to stabilized forms of the HIV gpl20 envelope protein in complex with the broadly neutralizing CD4-binding site antibody bl2, to crystalline forms of the stabilized forms of the HIV gpl20 envelope protein in complex with the broadly neutralizing CD4- binding site antibody b 12, and to the high resolution structure obtained from these crystals by X-ray diffraction methods. Methods for identifying immunogenic polypeptides based on these structures are also disclosed.
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STABILIZATION OF ORGANOGELS AND HYDROGELS BY AZIDE-ALKYNE[2+3] CYCLOADDITION (Fri, 09 Mar 2007)
Self-assembled gels were modified by the installation of azide and alkyne groups on the gelator and reaction with complementary reagents by the catalyzed azide-alkyne cycloaddition reaction. This is the first example of the use of a 'click' reaction in such a supramolecular environment, and a new strategy for tuning the properties of gelled materials .
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Variants and chemically-modified variants of phenylalanine ammonia-lyase (Fri, 02 Mar 2007)
The present invention pertains to the use of the protein phenylalanine ammonia-lyase, as well as the biologically-active derivatives of the said protein for preventing or treating diseases associated with a phenylalanine imbalance in a human or animal body. More particularly, the present invention relates to the therapeutic use of the above-cited molecules for preventing or treating a phenylalanine imbalance in vivo. This invention also deals with therapeutic compositions comprising a pharmaceutically active amount of the above-described therapeutic molecules as well as with therapeutic methods using the said therapeutic compositions. Finally, the present invention relates to processes for selecting more therapeutically-effective variants of said protein as well as to the selected variants themselves.
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Human aminoacyl-tRNA synthetase polypeptides useful for the regulation of angiogenesis (Fri, 02 Mar 2007)
Nucleic acids encoding tRNA synthetase polypeptides useful for regulating angiogenesis are disclosed. Methods of making and using such nucleic acids are also disclosed. 
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METHODS TO IDENTIFY THERAPEUTIC AGENTS USEFUL FOR TREATING AND PREVENTING ATHEROSCLEROSIS BY COUNTERACTING THE EFFECT OF CHOLESTEROL OZONATION PRODUCTS (Fri, 23 Feb 2007)
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.
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COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS (Fri, 23 Feb 2007)
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 PDGFRβ kinases.
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Kinase inhibitor scaffolds and methods for their preparation (Wed, 14 Feb 2007)
General methods for the solution phase as well as solid phase synthesis of various substituted heteroaryls has been demonstrated. These substituted heteroaryls can be further elaborated by aromatic substitution with amines at elevated temperature or by anilines, boronic acids and phenols via palladium catalyzed cross-coupling reactions.
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METHOD FOR MAKING AMPHIPHILIC DENDRIMERS (Fri, 26 Jan 2007)
A series of AB-type amphiphilic dendritic polyesters have been prepared divergently, in which two hybrids were coupled via the copper(l)-catalyzed triazole formation.
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METHOD OF USING CLICK CHEMISTRY TO FUNCTIONALIZE DENDRIMERS (Fri, 26 Jan 2007)
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(l)-catalyzed 1 ,3-dipolar cycloaddition of azides and terminal acetylenes.
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COMPOSITIONS AND METHODS FOR COUPLING A PLURALITY OF COMPOUNDS TO A SCAFFOLD (Fri, 26 Jan 2007)
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.
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Synthesis of synthons for the manufacture of bioactive compounds (Fri, 19 Jan 2007)
The present invention is based on the discovery that 2-deoxyribose-5-phosphate aldolase (DERA, EC 4.1.2.4) and variants thereof can be used to catalyze sequential asymmetric aldol reactions between a wide variety of donor and acceptor aldehydes. The reaction products typically contain at least two new stereogenic centers and can be produced in enantiomerically pure form. As such, DERA catalyzed asymmetric aldol chemistry can be exploited to produce synthons for the synthesis of a variety of bioactive molecules. 
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COMPUTER-ASSISTED METHOD FOR IDENTIFYING POTENTIAL MIMETICS OF ERYTHROPOIETIN (Mon, 01 Jan 2007)

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Analogs of epothilone (Fri, 29 Dec 2006)
Designed epoxide and cyclopropane epothilone analogs with substituted side-chains are disclosed and characterized with respect to their biological activities against a series of human cancer cell lines. Among the several bioactive analogs, the epothilone B analog with a thiomethyl thiazole ring stands out as the most potent. 
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Enhanced indolinone based protein kinase inhibitors (Fri, 22 Dec 2006)
Hydroxy carboxy pyrrolyl-indolinone 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. More particularly, 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 with respect to their corresponding beta-hydroxy-omega-(2-oxo-indolylidenemethyl-pyrrole-3′-carbonyl) amino alkanoic acid and amide derivatives and are useful in treating disorders related to abnormal protein kinase activities such as cancer. 
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COMPOUNDS THAT MAINTAIN PLURIPOTENCY OF EMBRYONIC STEM CELLS (Fri, 22 Dec 2006)
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.
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CRYSTAL OF A CYTOCHROME-LIGAND COMPLEX AND METHODS OF USE (Fri, 08 Dec 2006)
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.
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Methods for inhibition of angiogenesis (Fri, 01 Dec 2006)
The present invention describes methods for inhibition angiogenesis in tissues using organic peptidomimetic αvβ3 antagonists, and particularly for inhibiting angiogenesis in inflamed tissues and in tumor tissues and metastases using therapeutic compositions containing αvβ3 antagonists. The antagonists are organic compounds having a basic group and an acidic group spaced from one another by a distance in the range of about 10 Angstroms to about 100 Angstroms, as described in detail herein. 
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ENHANCED INDOLINONE BASED PROTEIN KINASE INHIBITORS (Fri, 01 Dec 2006)
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.
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Enzymatic DNA molecules (Wed, 29 Nov 2006)
The present invention discloses deoxyribonucleic acid enzymes—catalytic or enzymatic DNA molecules—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.
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6″-amino-6″-deoxygalactosylceramides (Fri, 24 Nov 2006)
This invention relates to galactosylceramide compounds.
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PYRROLOPYRIDINE DERIVATIVES AS PROTEIN KINASE INHIBITORS (Fri, 24 Nov 2006)
The invention provides a novel class of compounds, 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 CDKs, Aurora, Jak2, Rock, CAMKII, FLT3, Tie2, TrkB, FGFR3 and KDR kinases.
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COMPOSITIONS AND METHODS FOR MODULATING CELLS VIA CD14 AND TOLL-LIKE RECEPTOR 4 SIGNALING PATHWAY (Fri, 17 Nov 2006)
Compositions and methods are provided for screening and identifying compounds which modulate signaling of toll-like receptor 4 (TLR4) pathway via CD 14 and a ligand. Methods are provided for treatment of various disease states such as inflammation or autoimmune disease in mammalian subjects by modulating toll-like receptor 4 (TLR4) pathway signaling via CD 14 and a ligand. Transgenic non-human animals and methods for developing transgenic non-human animals are provided wherein the transgenic non-human animals comprise a loss-of-function mutation in the CD 14 gene.
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Unnatural reactive amino acid genetic code additions (Fri, 03 Nov 2006)
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-tRNAsyn-thetases, pairs of tRNAs/synthetases and unnatural amino acids. Proteins and methods of producing proteins with unnatural amino acids in eukaryotic cells are also provided.
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METHODS AND COMPOSITIONS FOR MODULATING WNT SIGNALING PATHWAY (Fri, 03 Nov 2006)
This invention provides novel Wnt signaling pathway regulators. The invention also provides methods of using the Wnt signaling pathway regulators to screen for compounds that modulate Wnt signaling pathway. The methods comprise first screening test compounds for modulators of a Wnt signaling pathway regulator disclosed herein, and then further screening the identified modulating agents for ability to modulate Wnt signaling pathway. The invention further provides methods for modulating Wnt signaling pathway and pharmaceutical compositions for treating diseases and conditions (e.g., tumors) associated with abnormal Wnt signaling activities.
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METHODS FOR METABOLITE PROFILING (Fri, 27 Oct 2006)
A method for metabolite profiling is provided including analyzing metabolites using untargeted liquid chromatography-mass spectroscopy.
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COMPOSITIONS AND METHODS FOR STABILIZING TRANSTHYRETIN AND INHIBITING TRANSTHYRETIN MISFOLDING (Thu, 26 Oct 2006)
 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, screening methods, as well as specific transthyretin stabilizing compounds are disclosed
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In vivo incorporation of unnatural amino acids (Fri, 20 Oct 2006)
The invention provides methods and compositions for in vivo incorporation of unnatural amino acids. Also provided are compositions including proteins with unnatural amino acids.
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Methods and composition for the production of orthogonal tRNA-aminoacyltRNA synthetase pairs (Fri, 20 Oct 2006)
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.
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ORTHOGONAL TRANSLATION COMPONENTS FOR THE IN VIVO INCORPORATION OF UNNATURAL AMINO ACIDS (Fri, 20 Oct 2006)
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 E.coli, 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.
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Human aminoacyl-tRNA synthetase polypeptides useful for the regulation of angiogenesis (Fri, 29 Sep 2006)
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.
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METHODS AND COMPOSITIONS FOR TREATING INSULIN RESISTANCE AND OBESITY-INDUCED DISEASES (Fri, 29 Sep 2006)
This invention provides novel methods for identifying compounds that are useful in modulating insulin signaling activities or treating insulin resistance and other obesity-induced diseases. The modulators are identified by screening test compounds for ability to modulate G protein coupled receptor GPR43 or GPR41. Such GPR43 or GPR41 modulators can be further examined for their activity in modulating insulin signaling (e.g., ameliorating insulin resistance). Pharmaceutical compositions comprising compounds that modulate GPR41 or GPR 43 receptor activity or expression level can be administered to a subject to modulate insulin signaling related activities, and to treat obesity-induced diseases or conditions including insulin resistance and diabetes.
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Methods for inhibiting angiogenesis and tumor growth (Fri, 22 Sep 2006)
Angiogenesis, tumor growth, and metalloproteinase 2 (MMP2) interaction with integrin-αvβ3 are inhibited by an inhibitor compound of formula: <chemistry id="chem-us-00001-en" num="00001"> <img id="emi-c00001" he="77.47mm" wi="75.95mm" file="US07368478-20080506-C00001.TIF" alt="embedded image" img-content="chem" img-format="tif"/> </chemistry> wherein G1 and G2 are each independently —NH—C(O)—O—(CH2)v—(C6H4)—X3 ; Y1 and Y2 are each independently —OH or C1-C4 alkoxy; X1 and X2 are each independently halo or C1-C4 alkoxy; X3 is fluoro, nitro, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 perfluoroalkyl; Z is —C≡C—, —C6H4—, cis-CH═CH—, trans-CH═CH—, cis-CH2—CH═CH—CH2—, trans-CH2—CH═CH—CH2—, 1,4-naphthyl, cis-1,3-cyclohexyl, trans-1,3-cyclohexyl, cis-1,4-cyclohexyl, or trans-1,4-cyclohexyl; A is H or a covalent bond; m and n are each 1; t is an integer having a value of 0 or 1; p and r are each 2, and v is 1; with the proviso that when A is H, t is 0, and when A is a covalent bond, t is 1. 
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Scaffolds for α-helix mimicry (Fri, 15 Sep 2006)
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.
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COMPOSITIONS AND METHODS FOR TREATMENT OF AUTOIMMUNE AND RELATED DISEASES (Sat, 09 Sep 2006)
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.
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COMPOSITIONS AND METHODS FOR TARGETING OR IMAGING A TISSUE IN A VERTEBRATE SUBJECT (Sat, 09 Sep 2006)
Compositions and methods are provided for targeting or imaging to a tumor or organ in a vertebrate subject. A plant viral particle for targeting and imaging and methods for treatment of disease are also provided.
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INHIBITORS OF TRANSTHYRETIN AMYLOID FIBRIL FORMATION (Fri, 18 Aug 2006)
Bisaryloxime ethers and bisarylhydroazones are shown to be effective for inhibiting formation of amyloid fibrils of transthyretin.
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Inhibitors of transthyretin amyloid fibril formation (Fri, 11 Aug 2006)
Bisaryloxime ethers and bisarylhydroazones are shown to be effective for inhibiting formation of amyloid fibrils of transthyretin.
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DYSLIPOPROTEINEMIA ASSOCIATED WITH VENOUS THROMBOSIS (Fri, 11 Aug 2006)
The present invention provides methods of determining a human subject’s risk for venous thrombosis based on the finding that venous thrombosis patients have significantly lower levels of large HDL particles, HDL-cholesterol and apolipoprotein AI and higher levels of small LDL particles, LDL-cholesterol and apolipoprotein B. Genotyping showed that venous thrombosis patients differed significantly from controls in CETP genotype and that the CETP genotypes found in subjects with VTE are linked to elevated CETP mass and activity. Methods for determining the level of lipids or lipoproteins in plasma or serum samples to determine risk for venous thrombosis are provided. Methods for reducing the risk of venous thrombosis are also provided.
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BACTERIAL GLYCOLIPID ACTIVATION OF CD1D-RESTRICTED NKT CELLS (Fri, 11 Aug 2006)
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.
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Methods and compositions useful for inhibition of alpha v beta 5 mediated angiogenesis (Fri, 28 Jul 2006)
The present invention describes methods for inhibiting angiogenesis in tissues using vitronectin αvβ5 antagonists. The αvβ5-mediated angiogenesis is correlated with exposure to cytokines including vascular endothelial growth factor, transforming growth factor-α and epidermal growth factor. Inhibition of αvβ5-mediated angiogenesis is particularly preferred in vascular endothelial ocular neovascular diseases, in tumor growth and in inflammatory conditions, using therapeutic compositions containing αvβ5 antagonists. 
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COMPOUNDS AND COMPOSITIONS AS WNT SIGNALING PATHWAY MODULATORS (Fri, 28 Jul 2006)
The invention provides a novel class of compounds and methods of using such compounds to study the activity of the Wnt signaling pathway.
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GLYCOLIPIDS AND ANALOGUES THEREOF AS ANTIGENS FOR NK T CELLS (Fri, 07 Jul 2006)
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.
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SYNTHESIS OF THE DIHYDROINDOLE C - RING TO THE CC-1065/DUOCARMYCIN ANALOG (Thu, 06 Jul 2006)

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INHIBITORS OR FATTY ACID AMIDE HYDROLASE (Thu, 29 Jun 2006)
Improved competitive inhibitors of FAAH employ an a-keto heterocyclic pharmacophore and a binding subunit having a ?-unsaturation. The α-keto heterocyclic pharmacophore and a binding subunit are attached to one another, preferably by a hydrocarbon chain. The improvement lies in the use of a heterocyclic pharmacophore selected from oxazoles, oxadiazoles, thiazoles, and thiadiazoles that have alkyl or aryl substituents at their 4 and/or 5 positions. The improved competitive inhibitors of FAAH display enhanced activity over conventional competitive inhibitors of FAAH.
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Adding photoregulated amino acids to the genetic code (Fri, 23 Jun 2006)
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 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. 
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Targeted delivery to legumain-expressing cells (Fri, 23 Jun 2006)
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.
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Methods and compositions useful for inhibition of αvβ5mediated angiogenesis (Wed, 31 May 2006)
The present invention describes methods for inhibiting angiogenesis in tissues using vitronectin αvβ5 antagonists. The αvβ5-mediated angiogenesis is correlated with exposure to cytokines including vascular endothelial growth factor, transforming growth factor-α and epidermal growth factor. Inhibition of αvβ5-mediated angiogenesis is particularly preferred in vascular endothelial ocular neovascular diseases, in tumor growth and in inflammatory conditions, using therapeutic compositions containing αvβ5 antagonists.
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SUBNANOMOLAR PRECIPITATOR OF THIOPHILIC METALS (Sat, 27 May 2006)
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 Hg2+ using a conventional fluorescence microscope.
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Site-specific labeling of proteins for NMR studies (Fri, 26 May 2006)
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. 
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In vivo site-specific incorporation of N-acetyl-galactosamine amino acids in eubacteria (Fri, 26 May 2006)
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.
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Inhibitors of fatty acid amide hydrolase (Fri, 26 May 2006)
Improved competitive inhibitors of FAAH employ an α-keto heterocyclic pharmacophore and a binding subunit having a ?-unsaturation. The α-keto heterocyclic pharmacophore and a binding subunit are attached to one another, preferably by a hydrocarbon chain. The improvement lies in the use of a heterocyclic pharmacophore selected from oxazoles, oxadiazoles, thiazoles, and thiadiazoles that have alkyl or aryl substituents at their 4 and/or 5 positions. The improved competitive inhibitors of FAAH display enhanced activity over conventional competitive inhibitors of FAAH.
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Oxadiazole ketone inhibitors of fatty acid amide hydrolase (Fri, 12 May 2006)
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).
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COMPOUNDS AND COMPOSITIONS AS HEDGEHOG PATHWAY MODULATORS (Fri, 12 May 2006)
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.
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IN VIVO SITE-SPECIFIC INCORPORATION OF N-ACETYL-GALACTOSAMINE AMINO ACIDS IN EUBACTERIA (Fri, 28 Apr 2006)
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-cetylgalactosamine moiety into a protein; optionally, the N-acetylgalactosamine-containing unnatural amino acid can be further modified with additional sugars.
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OXADIAZOLE KETONE INHIBITORS OF FATTY ACID AMIDE HYDROLASE (Fri, 28 Apr 2006)
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).
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In vivo incorporation of alkynyl amino acids into proteins in eubacteria (Fri, 07 Apr 2006)
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 E. coli. The invention provides novel orthogonal synthetases, methods for identifying and making the novel synthetases, methods for producing proteins containing alkynyl amino acids, and cellular translation systems.
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SITE-SPECIFIC LABELING OF PROTEINS FOR NMR STUDIES (Fri, 07 Apr 2006)
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.
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Site specific incorporation of keto amino acids into proteins (Fri, 31 Mar 2006)
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.
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VARIANTS AND CHEMICALLY-MODIFIED VARIANTS OF PHENYLALANINE AMMONIA-LYASE (Fri, 31 Mar 2006)
The present invention pertains to the use of the protein phenylalanine ammonia-lyase, as well as the biologically-active derivatives of the said protein for preventing or treating diseases associated with a phenylalanine imbalance in a human or animal body. More particularly, the present invention relates to the therapeutic use of the above-cited molecules for preventing or treating a phenylalanine imbalance in vivo. This invention also deals with therapeutic compositions comprising a pharmaceutically active amount of the above-described therapeutic molecules as well as with therapeutic methods using the said therapeutic compositions. Finally, the present invention relates to processes for selecting more therapeutically-effective variants of said protein as well as to the selected variants themselves.
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