Torrey Pines Institute for Molecular Studies

Other

University of California

The Scripps Research Institute

Lion Bioscience Ag

Houghten Pharmaceuticals, Inc.

Osterreichische Akademie Der Wissenschaften

Torry Pines Institute for Molecular Studies

Torrey Pines Institute

Pba3 Biomed Gmbh

Sylvie E Blondelle

Richard Allen Houghten

Enrique Perez-Paya

John M Ostresh

Mauricio Montal

Massimo Porro

Clemencia Pinilla

Jean-Philippe Meyer

Colette Dooley

Karl Lohner

Dagmar Zweytick

Klaus Brandenburg

Roman Jerala

Antonio Ferrer-Montiel

Jaime Merino

Christa C Schoner

Kwok-Keung Tai

Jose Leiva Leon

Gunter Deutsch

Guillermo Martinez De Tejada De Garaizabal

Ignacio Moriyon Uria

Jorg Andra

Bostjan Japelj

Mateja Zorko

Andreja Majerle

Primoz Pristovsek

Guenter Deutsch

Joerg Andrae

The present invention relates to families of polypeptides and lipopolypeptides that have antimicrobial and endotoxin-neutralizing activities. These molecules show a broad spectrum of activity against various pathogens (including bacteria, viruses, fungi etc.) These compounds can be used alone or in combination therapy with conventional antibiotics or antiendotoxic agents. In addition, the present invention discloses processes for making and using of the compounds.

Antimicrobial peptides

Neuroprotectant agents are provided which do not contain peptides and axe protected from the degradation that limits the use of peptide-based drugs in systemic circulation. With great selectivity for NMDA receptors, the agents exert an open channel block on NMDA receptors, and protect neuronal cells containing such receptors from excitatoxic cell death.

NMDA receptor channel blocker with neuroprotective activity

The invention provides a rapid approach for combinatorial synthesis and screening of combinatorial libraries of bicyclic guanidine compounds. The present invention further provides the compounds made by the combinatorial synthesis and individually as well as methods of using the same.

Combinatorial libraries of bicyclic guanidine derivatives and compounds therein

Compounds that provide protection against excitotoxic neuronal damage are selected from the group consisting of Arg-rich oligopeptides and compounds of formula 1:

N-methyl-d-aspartate receptor channel blockers and method for identifying such

The present invention relates to novel family of peptides which inhibit calmodulin and which have the general structure Ac-A1-B2-C3-D4-E5-F6-NH.sub.2, (SEQ ID No. 1), wherein A1 is (D)Leu or Leu, B2 is (D)Gln, Gln, (D)Trp, or Trp, C3 is (D)Arg, Arg, (D)Ile, or Ile, D4 is (D)Ile, Ile, (D)His, or His, E5 is (D)Leu, Leu, (D)His, or His, and F6 is (D)Trp, Trp, (D)Arg, or Arg. The novel peptides can be used to inhibit the activity of calmodulin. In addition, the present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a calmodulin-inhibitor peptide. These compositions can be used to treat calmodulin related disorders.

Peptide inhibitors of calmodulin

Sets and libraries of sets of polypeptides that are related in sequence to melittin are disclosed that have antimicrobial, hemolytic and hydrolytically catalytic activities, as are processes for making and using the same. A contemplated set is a mixture of equimolar amounts of a polypeptide of SEQ ID NO:2, and more preferably SEQ ID NO:3.

Melittin-related polypeptides, mixture sets and libraries thereof

Linear C.sub.1 -C.sub.7 -alkyl peralkylated oligopeptide sets of molecules are disclosed, as are their methods of synthesis and use in acceptor binding assays. Each molecule or chain of a set contains the same number of two to about ten substituted C.sub.1 -C.sub.7 -alkyl peralkylated amino acid residues, and the member chains of a set are present in equimolar amounts. The chains of a set contain one or more predetermined peralkylated amino acid residues at one or more predetermined positions of the peralkylated oligopeptide chain. The set contains equimolar amounts of at least six different peralkylated amino acid residues at one or more of the same predetermined positions of the peralkylated oligopeptide chain. Libraries of such sets, processes for their use and solid support-linked peralkylated sets are also contemplated, as are specific permethylated oligopeptides.

Peralkylated oligopeptide mixtures

Disclosed are peptides having anti-mellitin activity and having the formulae AC-IVILZZ-NH.sub.2, wherein Z is an amino acid. Also disclosed are compositions containing these peptides and methods of using them.

Peptides having anti-melittin activity

Sets and libraries of sets of polypeptides that are related in sequence to melittin are disclosed that have antimicrobial, hemolytic and hydrolyrically catalytic activities, as are processes for making and using the same. A contemplated set is a mixture of equimolar amounts of a polypeptide of SEQ ID NO:2, and more preferably SEQ ID NO:3.

The present invention relates to novel family of peptides which inhibit calmodulin and which have the general structure Ac-(D)Leu-A1-B2-C3-D4-E5-NH.sub.2, wherein A1 is (D)Gln or (D)Trp, B2 is (D)Arg or (D)Ile, C3 is (D)Ile or (D)His, D4 is (D)Leu or (D)His and E5 is (D)Trp or (D)Arg. The novel peptides can be used to inhibit the activity of calmodulin. In addition, the present invention relates to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a calmodulin-inhibitor peptide. These compositions can be used to treat calmodulin related disorders.

Polypeptides, sets and libraries of sets of polypeptides that are related in sequence to the polypeptide of SEQ ID NO:1 are disclosed that have antimicrobial, hemolytic and hydrolytically catalytic activities, as are processes for making and using the same. A contemplated set is a mixture of equimolar amounts of a polypeptide of SEQ ID NO:2. Particularly preferred polypeptides include those of SEQ ID NOs:3-9.

Lysine/leucine polypeptides, mixture sets and libraries thereof

Linear C.sub.1 -C.sub.7 -alkyl peralkylated oligopeptide sets of molecules are specific peralkylated oligopeptides, disclosed, as are their methods of synthesis and use in acceptor binding assays. Each molecule or chain of a set contains the same number of two to about ten substituted C.sub.1 -C.sub.7 -alkyl peralkylated amino acid residues, and the member chains of a set are present in equimolar amounts. The chains of a set contain one or more predetermined peralkylated amino acid residues at one or more predetermined positions of the peralkylated oligopeptide chain. The set contains equimolar amounts of at least six different peralkylated amino acid residues at one or more of the same predetermined positions of the peralkylated oligopeptide chain. Libraries of such sets, processes for their use and solid support-linked peralkylated sets are also contemplated, as are specific permethylated oligopeptides such as those having 5-8 phenylalanine residues that have antimicrobial properties.

Peptides having Anti-microbial activity and having the formula (KFmoc)ZZZ-NH.sub.2, wherein Z is an amino acid are disclosed. Also disclosed are peptides having anti-trypsin activity and having the formula Ac-rypwz-NH.sub.2, wherein z is a D-amino acid. Also disclosed are compositions containing these peptides and methods of using them.

Peptides of the formula (KFmoc) ZZZ and their uses

A process for inhibiting growth of a target cell comprising administering to a host or to a target cell or virus a biologically active peptide which includes one of the following basic structures; R.sub.1 -R.sub.1 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 ; R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 ; or R.sub.1 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1, wherein R.sub.1 is a hydrophobic amino acid, and R.sub.2 is a basic hydrophilic or neutral hydrophilic amino acid. A preferred peptide is of the structural formula:

Amphiphilic peptide compositions and analogues thereof

A compound comprising an analogue of the melittin peptide having the following structural formula: ##STR1## wherein at least one and no more than four amino acid residues are omitted from the peptide, or at least one of amino acid residues 1-6, 8-18, or 20-26 in the peptide is substituted with a hydrophobic residue, provided that no more than two of amino acid residues 21-26 is substituted with a hydrophobic residue. Such deletion and substitution analogues are useful as antibiotics, antimicrobial agents, antifungal agents, anti-tumor agents, antiviral agents, or agents which stimulate wound healing.

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San Diego, CA, United States of America

Sylvie E Blondelle