Patents Represented by Attorney G. Lewis
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Patent number: 5958673Abstract: Fluorescent dyes possess reactive linkers for conjugating to nucleic acids, carbohydrates and peptides. The conjugates fluoresce in the visible and UV spectrum and have an excellant solvochromatic response as compared to other fluorescence or chromatic labels. The conjugates are stable but also have medium sensitive. The fluorescent dyes have little triplet state formation and are not photoreactive, making them an excellent substance for biological investigations. Uses for the dyes include protein labelling, DNA labelling, single molecule spectroscopy and fluorescence. A synthesis of the dyes is disclosed. Methods of use include the detection of carbohydrate-protein interactions.Type: GrantFiled: February 2, 1998Date of Patent: September 28, 1999Assignee: The Scripps Research InstituteInventor: James J. LaClair
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Patent number: 5939568Abstract: Rhenium-catalyzed epoxidation of olefinic substrates is accelerated by the use of acclerants having a nitrogenous aromatic heterocyclic structure. Use of the accelerants also enables the use of aqueous hydrogen peroxide as an oxidant. To achieve optimum acceleration, the accelerant should have a concentration within a range from 2.0 mole percent to 100 mole percent of the acclerant with respect to 1 mole of the olefinic substrate. Use of the accelerant also results in an increased yield with respect to the conversion of the olefinic substrate to epoxide product.Type: GrantFiled: April 16, 1997Date of Patent: August 17, 1999Assignee: The Scripps Research InstituteInventors: K. Barry Sharpless, Joachim Rudolph
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Patent number: 5929252Abstract: A method for the direct aziridination of olefins as well as a wide range of allylic alcohols employs phenyltrimethylammonium tribromide (PTAB) as a general and effective catalyst and N-sodio-N-chloro sulfonamides, chloramine salts, as the nitrogen source.Type: GrantFiled: June 15, 1998Date of Patent: July 27, 1999Assignee: The Scripps Research InstituteInventors: K. Barry Sharpless, Jae Uk Jeong
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Patent number: 5910437Abstract: D-enzyme compositions are described comprising an amino acid residue sequence that defines an polypeptide able to catalyze an enzymatic reaction. The D-enzyme has an amino acid residue sequence consisting essentially of D-amino acids.Type: GrantFiled: May 22, 1996Date of Patent: June 8, 1999Assignee: The Scripps Research InstituteInventors: Stephen Brian Henry Kent, Saskia Charlotte Florence Milton, Raymond Cecil deLisle Milton
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Patent number: 5891993Abstract: Disclosed herein are template assembled synthetic protein (TASP) molecules that contain dendritic linkage units having the structure .psi. (CO--S--CH.sub.2 --CO--NH). Also disclosed are methods of preparing the template assembled synthetic proteins.Type: GrantFiled: January 29, 1996Date of Patent: April 6, 1999Assignee: The Scripps Research InstituteInventors: Philip E. Dawson, Stephen B.H. Kent
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Patent number: 5876981Abstract: .beta.-Galactosides are synthesized using a transglycosylation reaction catalyzed by .beta.-galactosidase. The reaction employs a carbohydrate donor having a glycosidic leaving group attached to its anomeric carbon and an oxo group attached to the C-6 carbon. Strong leaving groups are preferred over weak leaving groups. The method can be carried out in aqueous solution without organic solvents to give the transglycosylation product in high yields and high regioselectivity. The synthesis of lactosamine using this methodology with galactose oxidase (GO) and .beta.-galactosidase has been accomplished. (FIG. 3). The methodology affords simple reaction conditions and minimal purification steps. In addition, the intermediate substrates maintain high stability, the process affords high yields and the enzymes and reagents employed are commercially available with high stability and low costs.Type: GrantFiled: October 17, 1996Date of Patent: March 2, 1999Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Teiji Kimura
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Patent number: 5869316Abstract: Aureobacterium barkeri strain KDO-37-2 (ATCC 49977) and KDO aldolase (EC 4.1.2.23) isolated therefrom are disclosed. The KDO aldolase is further disclosed to have a broad substrate specificity with respect to its reverse reaction, i.e. the condensation of aldoses with pyruvate to form a wide range of 2-keto-3-deoxy-onic acids, including 2-keto-3-deoxy-nonulosonic acid, 2-keto-3-deoxy-octulosonic acid, 2-keto-3-deoxy-heptulosonic acid, and 2-keto-3-deoxy-hexulosonic acid. In particular, 3-deoxy-D-manno-2-octulosonic acid (D-KDO), a vital component of lipopolysaccharides found in the bacterial outer membrane may be synthesized from D-arabinose and pyruvate in 67% yield. Additionally, protected forms of the KDO aldolase products, e.g. hexaacetyl 2-keto-3-deoxy-nonulosonic acid and pentaacetyl 2-keto-3-deoxy-octulosonic acid, may be decarboxylated to form the corresponding 2-deoxy-aldoses, e.g. 2-deoxy-octulose and 2-deoxy-heptulose respectively.Type: GrantFiled: December 16, 1996Date of Patent: February 9, 1999Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Takeshi Sugai, Gwo-Jenn Shen
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Patent number: 5859281Abstract: .beta.-Hydroxyamines and .beta.-hydroxysulfonamides are synthesized from olefin substrates by means on a catalyzed asymmetric addition reaction. The addition reaction is catalyzed by osmium and is co-catalyzed by chiral ligands. The chiral ligands, in addition to being co-catalysts with the osmium, also serve to direct the addition reaction regioselectively and enantioselectively. Divalent ligands are preferred over monovalent ligands because of their enhance regio- and enantio-selectivity. Sulfonamides are employed as an oxidant nitrogen source for the production of .beta.-hydroxysulfonamides. Excellent yields and enantiomeric efficiencies are achieved with co-solvents containing a 50/50 (v/v) mixtures of water and organic solvent. .beta.-Hydroxyamines are obtained by deprotecting the corresponding .beta.-hydroxysulfonamides.Type: GrantFiled: May 21, 1996Date of Patent: January 12, 1999Assignee: The Scripps Research InstituteInventors: K. Barry Sharpless, Guigen Li, Han-Ting Chang
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Patent number: 5856537Abstract: Inhibitors of oleamide hydrolase, responsible for the hydrolysis of an endogenous sleep-inducing lipid (1, cis-9-octadecenamide) were designed and synthesized. The most potent inhibitors possess an electrophilic carbonyl group capable of reversibly forming a (thio) hemiacetal or (thio) hemiketal to mimic the transition state of a serine or cysteine protease catalyzed reaction. In particular, the tight binding .alpha.-keto ethyl ester 8 (1.4 nM) and the trifluoromethyl ketone inhibitor 12 (1.2 nM) were found to have exceptional inhibitory activity. In addition to the inhibitory activity, some of the inhibitors displayed agonist activity which resulted in the induction of sleep in laboratory animals.Type: GrantFiled: June 26, 1996Date of Patent: January 5, 1999Assignee: The Scripps Research InstituteInventors: Richard A. Lerner, Chi-Huey Wong, Dale L. Boger, Steven J. Henriksen
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Patent number: 5854391Abstract: A method for synthesizing glycosylated peptides employs a blocked carbohydrate donor and a blocked peptide acceptor. The carbohydrate donor includes an acid labile phosphite leaving group attached to the anomeric carbon. The blocked peptide acceptor includes an unprotected hydroxyl group susceptible to electrophilic attack. Serine hydroxyl is preferred. The reaction is initiated by the addition of a Lewis acid so as to activate the acid labile phosphite leaving group on the carbohydrate donor. The substitution reaction may be conducted at -78.degree. C. in a solvent such as Et.sub.3 N which favors the formation of glycosylated peptide products.Type: GrantFiled: March 18, 1993Date of Patent: December 29, 1998Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Hirosato Kondo
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Patent number: 5854389Abstract: Process for the preparation of modified proteins comprising the coupling of a first peptide segment having a haloacyl group at the N-terminus thereof with a second peptide segment having a carbonylthiol group at the C-terminus thereof are disclosed. Novel modified proteins produced by the process are also disclosed.Type: GrantFiled: September 26, 1994Date of Patent: December 29, 1998Assignee: The Scripps Research InstituteInventors: Stephen B. H. Kent, Martina Schnolzer-Rackwitz
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Patent number: 5837862Abstract: Sialyl Lewis X mimetics based on mannose glycosides are synthesized and shown to mimic the configuration and essential functional groups of sialyl Lewis X in space. The mannose based mimetics exhibit comparable biological activity as sialyl Lewis X in the E- selectin binding assay and can be employed for blocking neutrophil inflamatory conditions.Type: GrantFiled: December 12, 1996Date of Patent: November 17, 1998Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Thomas G. Marron, Thomas J. Woltering, Gabriele Weitz-Schmidt
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Patent number: 5830871Abstract: Inhibitors of E-, P- and L-selectin binding are synthesized by an aldol addition reaction between a glycoside aldehyde precursor and dihydroxyacetone phosphate or a derivative thereof. The addition reaction is catalyzed by aldolase. The inhibitors exhibit an activity comparable to sialyl Lewis X with respect to the E-selectin binding assay and high activities in the P- and L-selectin binding assays. The inhibitors are employable for blocking neutrophil inflamatory conditions.Type: GrantFiled: October 28, 1996Date of Patent: November 3, 1998Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Francisco Moris-Varas, Chun-Cheng Lin
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Patent number: 5827827Abstract: A series of novel oxirane derivatives, which are useful for inhibiting HIV are disclosed. Particularly of value are peptidomimetic compounds, containing a terminal epoxide group on a peptide or psuedopeptide backbone, which are believed to inhibit HIV protease by extruding enzyme-bound water molecules from the active site of the enzyme.Type: GrantFiled: June 20, 1996Date of Patent: October 27, 1998Assignee: The Scripps Research InstituteInventors: Kim D. Janda, Peter Wirsching
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Patent number: 5817840Abstract: Alkaline sensitive protaxol is water soluble and is hydrolyzed at physiological (alkaline) pH to render the native taxol structure and the native taxol activity. Protaxol compositions include 2'- and/or 7-O-ester derivatives of taxol and/or 2'- and/or 7-O-carbonate derivatives taxol. Protaxol has a formula as follows: ##STR1## wherein R.sup.1 and R.sup.2 are each H or a radical selected from the group consisting of --CO--(CH.sub.2).sub.m --X--(CH.sub.2).sub.n --COZ and --COO--(CH.sub.2).sub.o --Y--Ar, and wherein m, n, and o are each an integer of 1 to 3; X is 0, S, NH, SO, or SO.sub.2 ; Y is S, SO or SO.sub.2 ; Ar is phenyl or substituted phenyl wherein the substituent is halo, amino, nitro or N,N-dialkylamino having 1 to 4 carbons in each of the alkyl groups; and Z is OH, OR.sup.3, SR.sup.3 or NR.sup.4 R.sup.5 wherein R.sup.3 is alkyl containing 1 to 4 carbons and R.sup.4 and R.sup.Type: GrantFiled: March 4, 1997Date of Patent: October 6, 1998Assignee: The Scripps Research InstituteInventors: K. C. Nicolaou, Claus G. Riemer, Michael A. Kerr
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Patent number: 5807979Abstract: Methods for synthesizing three-dimensional stabilized peptides which mimic the three-dimensional configuration of the active site of a natural, biologically active protein are carried out by (1) noting the three-dimensional configuration of the active site of a known biologically active protein (2) noting the amino acid sequence and the hydrogen bonds existing between amino acids which hydrogen bonds are capable of maintaining the three-dimensional configuration of the active site and (3) producing a synthetic three-dimensional peptide to mimic the structure of the active site. The synthetic peptide is synthesized so as to have the same or a similar amino acid sequence to the amino acid sequence of the active site of the biologically active polypeptide but with the stabilizing hydrogen bonds being replaced by a bridging divalent radical selected from the group of --(N)--C(CH.sub.3).dbd.N(H.sup.+)--CH.sub.2 --(N)--; --(N)--C(CH.sub.3).dbd.N(H.sup.+)--CH.sub.2 --CH.sub.2 --(N)--; and --(N)--N.dbd.CH--CH.sub.Type: GrantFiled: June 1, 1995Date of Patent: September 15, 1998Assignee: The Scripps Research InstituteInventors: Arnold C. Satterthwait, Jr., Thomas Arrhenius, Lin-Chang Chiang, Edelmira Cabezas
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Patent number: 5786489Abstract: A method for esterifying C13 deoxy taxoid intermediates employs three steps, i.e., oxygenation of the C13 deoxy taxoid intermediate to produce a C13 enone taxoid intermediate; reduction of the C13 enone to produce an alcohol; followed by esterification of the C13 alcohol. Key intermediates include C13 deoxy taxoids; C13 enone substituted taxoids; and C1-C2 cyclo carbonate esters of taxoids.Type: GrantFiled: April 1, 1996Date of Patent: July 28, 1998Assignee: The Scripps Research InstituteInventors: Kyriacos C. Nicolaou, Philippe G. Nantermet, Rodney K. Guy, Hiroaki Ueno
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Patent number: 5770407Abstract: Nucleotide linked 2-deoxy-2-fluoroglycosides are employed as potent competitive inhibitors of glycosyltransferases. More particularly, uridine-5'-diphospho-2-deoxy-2-fluoro-galactose (UDP-2F-Gal), guanidine-5'-diphospho-2-deoxy-2-fluoro-L-fucose (GDP-2F-Fuc), uridine-51-diphospho-2-deoxy-2-fluoro-D-glucose (UDP-2F-Glu), guanosine-5'-diphospho-2-deoxy-2-fluoro-D-mannose (GDP-2F-Man), cytosine-5'-monophospho-2-deoxy-2-fluoro-D-sialic acid, and cytosine-5'-monophospho-2-deoxy-2-KDO may be employed as inhibitors of .beta.-1,4-galactosyltransferase, .alpha.-1,3-fucosyltransferase, glucosyltransferases, N-acetylglucosaminyltransferases, (.alpha.-mannosyltransferases, .alpha.-sialyltransferases, and KDO-transferases, respectively. Synthesis of nucleotide-linked-2-deoxy-2-fluoroglycosides is achieved using either chemoenzymatic or chemical methodologies.Type: GrantFiled: December 10, 1996Date of Patent: June 23, 1998Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Takashi Hayashi
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Patent number: 5766887Abstract: Regioselective acetylation of the 9-hydroxyl group on N-acetylneuraminic acid is achieved enzymatically for producing oligosaccharides which contain a terminal N-acetylneuraminic acid moiety. This method provides access to O-acylated disialogangliosides as well as other N-acetyl-neuraminic acid oligosaccharides. These compounds are biologically and medicinally important and are difficult to obtain from nature or by chemical acylations. The methodology affords simple reaction conditions and minimal purification steps. In addition, the process affords good yields and the enzymes and reagents employed are commercially available with high stability and low costs.Type: GrantFiled: August 26, 1996Date of Patent: June 16, 1998Assignee: The Scripps Research InstituteInventors: Chi-Huey Wong, Shuichi Takayama
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Patent number: 5767304Abstract: .beta.-Hydroxyamines and .beta.-hydroxycarbamates are synthesized from olefin substrates by means on a catalyzed asymmetric addition reaction. The addition reaction is catalyzed by osmium and is co-catalyzed by chiral ligands. The chiral ligands, in addition to being co-catalysts with the osmium, also serve to direct the addition reaction regioselectively and enantioselectively. Divalent ligands are preferred over monovalent ligands because of their enhance regio- and enantio-selectivity. Carbamates are employed as an oxidant nitrogen source for the production of .beta.-hydroxysulfonamides. Excellent yields and enantiomeric efficiencies are achieved with co-solvents containing a 50/50 (v/v) mixtures of water and organic solvent. The performance of the reaction is further enhanced by omitting the addition silver or mercurial salts conventionally employed in asymmetric aminohydroxylation additions to olefins performed in neat or substantially neat solvents. .beta.Type: GrantFiled: May 21, 1996Date of Patent: June 16, 1998Assignee: The Scripps Research InstituteInventors: K. Barry Sharpless, Guigen Li