University of California

Chiron Corporation

Novartis Vaccines & Diagnostics, Gmbh

Fred Ehrenkranz Cohen

Stanley B Prusiner

James H McKerrow

George Lommel Kenyon

Zhe Li

Ronald N Zuckermann

Michael A Innis

Tetsuo Uno

John E Murphy

Glenn C Telling

Varavani J Dwarki

Nathalie Dubois-Stringfellow

Michael R Scott

Kiyotoshi Kaneko

Xiaohui Du

Xiaowu Chen

Rongshi Li

Chun Guo

Baoqing Gong

Christine Sun Ring

Philip Jon Rosenthal

Thomas L James

Michael Glenn Scott

Jiri G Safar

Gordon J Strewler

Robert A Nissenson

Tamaki Muramoto

Kivotoshi Kaneko

Thomas R Defay

The present invention relates to thio semicarbazone and semicarbazone inhibitors of cysteine proteases and methods of using such compounds to prevent and treat protozoan infections such as trypanosomiasis, malaria and leishmaniasis. The compounds also find use in inhibiting cysteine proteases associated with carcinogenesis, including cathepsins B and L.

Thio semicarbazone and semicarbozone inhibitors of cysteine proteases and methods of their use

This invention relates compositions and methods for increasing the uptake of polynucleotides into cells. Specifically, the invention relates to vectors, targeting ligands, and polycationic agents. The polycationic agents are capable of (1) increasing the frequency of uptake of polynucleotides into a cell, (2) condensing polynucleotides; and (3) inhibiting serum and/or nuclease degradation of polynucleotides.

Compositions and methods for polynucleotide delivery

Thio semicarbazone and semicarbazone inhibitors of cysteine proteases and methods of their use

Assay methodology of the invention allows for: (1) determining if a sample contains a conformation of a protein which is associated with disease and the concentration and amount of such if present; (2) determining the amount of protease resistant disease related protein in a sample and by subtracting that amount from the total amount of disease related protein present determining the amount of protease sensitive disease protein in the sample; and (3) determining the strain and incubation time of a disease related protein by (i) relating the relative amounts of protease resistant and protease sensitive protein to known strains to thereby determine the strain; and (ii) plotting the concentration of protease sensitive protein on a graph of incubation time versus concentration of protease sensitive protein for known strains to predict the incubation time of an unknown strain of pathogenic protein in a sample.

Assay for specific strains of multiple disease related conformations of a protein

DNA constructs are provided of epitope-tagged proteins or protein fragments which are conveniently purified with immunoaffinity chromatography such as epitope-tagged prion proteins (PrP). Transgenic animals expressing an epitope-tagged protein are provided, including transgenic animals expressing epitope-tagged PrP. Methods for distinguishing between the conformational shapes of a protein and a convenient method for isolating a tagged protein by immunoaffinity chromatographic methods are provided.

Recombinant construct encoding epitope tagged PrP protein

Inhibitors of metazoan parasite proteases

Molecules are disclosed that interact with the cellular components involved in conversion of PrP to PrP . The molecules disclosed can be small molecules, peptides or protein analogs, e.g. analogs of PrP . In one embodiment, these molecules interfere with prion formation and/or replication, e.g. by preventing interactions of proteins involved in a prion complex or by interfering with &bgr;-sheet formation. In another embodiment, the molecules of the invention promote PrP conversion to PrP , e.g. by binding to PrP and facilitating a conformational change from PrP to PrP .

Inhibitors of prion formation

Polycationic polymers

Transgenic animals expressing artificial epitope-tagged proteins

A protein designated Prion Protein Modulator Factor (PPMF) is disclosed which protein is an auxiliary factor in prion replication. PPMF is primarily characterized by its ability to bind to PrP.sup.C and facilitate a conformational change from PrP.sup.C to PrP.sup.Sc. A discontinuous epitope on PrP.sup.C comprising residues 172, 215 and 219 of human PrP.sup.C binds PPMF which is encoded by a nucleotide sequence derived from an organism selected from the group consisting of cow, sheep, mouse, hamster and human. In converting PrP.sup.C to PrP.sup.Sc the PPMF forms a PrP.sup.C /PrP.sup.Sc complex and is a rate limiting compound in the formation of that complex. Molecules, including antibodies, which bind PPMF or its epitope on PrP.sup.C are useful in the treatment of prion disease. Pharmacophores of the PrP.sup.C epitope are disclosed as are useful therapeutics and pharmacophores of the PPMF surface which binds PrP.sup.C. Animals resistant to prion disease are taught as are genes for producing such animals. Assay systems are disclosed which use PPMF to amplify PrP.sup.Sc is a sample being tested.

Nucleic acid encoding prion protein variant

The present invention pertains to a system and method for predicting the protein fold of a target amino acid residue sequence of unknown protein structure. A target sequence is represented by a sequence of residue variability types that utilizes positional variability information present in an associated family of homologous sequences to the target sequence. The use of the positional variability information increases the likelihood of matching the target sequence with a known protein structure. In a first preferred embodiment, a target sequence is mapped into a sequence of residue variability types that are based on the solubility variability present between amino acid residues in homologous sequences. In a second preferred embodiment, each residue variability type represents a cluster of residue types at each position of aligned sets of homologous protein sequences. Each distinct cluster represents a pattern of residue variability at various positions in sets of homologous protein sequences. The sequence of residue variability types is aligned with one or more environment strings, each of which represents a known protein structure in accordance with the degree of surface exposure for each amino acid position in the protein's structure. The alignment is performed using a threading procedure that determines a score for each alignment indicating the compatibility of the sequence to the structure. The protein structure associated with the highest score is deemed to be the most analogous structure to the target sequence.

System and method for determining three-dimensional structure of protein

The present invention relates polypeptide analogs which have agonist or antagonist or tissue selection properties relative to parathyroid hormone (PTH), parathyroid hormone-like protein (PLP) or parathyroid-related protein (PTHrP). The serine amino acid at position 3, the glutamine amino acid at position 6, the histidine amino acid at position 9 or combinations thereof are substituted by other natural or synthetic amino acids. Preferably, a human PTH fragment of about 34 amino acids is sufficient for pharmacological activity. These polypeptides are useful as agonists or antagonists in the treatment of a human being for disease conditions of cancer, osteoporosis, hypercalcemia, or hyperparathyroid disease conditions. The invention also concerns a method of performing certain assays using the modified peptides, and based on the results of the assays falling within preset limits, selecting those modified peptides which shall be useful in the treatment of disease conditions.

Parathyroid hormone analogues useful for treatment of osteoporosis and

The invention includes deleting codon segments from DNA expressing a native protein (e.g., PrP.sup.Sc) in order to obtain a shorter, soluble protein which mimics characteristics of an insoluble native (e.g., PrP.sup.Sc) protein. Soluble proteins of the invention are characterized by: (1) having less amino acids than the full length native protein; (2) having a higher degree of solubility than the native protein; (3) retaining the basic biological characteristics of the native protein such as (a) not being subject to enzymatic digestion and (b) causing disease. Soluble proteins of the invention are obtained by providing a DNA sequence which encodes a native protein and systematically removing codons, making copies of the shortened versions of DNA which are then expressed to provide the shortened proteins. The shortened proteins are then tested for solubility. Soluble proteins are then further tested to confirm that they retain the biological characteristics of the native protein. The soluble form can also be created by adding amino acids, binding a hydrophilic moiety to the native protein or combinations of deleting, adding, and binding hydrophilic moieties to the protein.

Soluble form of PrP.sup.SC which is insoluble in native form

Growing community of inventors

San Francisco, CA, United States of America

Fred Ehrenkranz Cohen