Duke University

National Institutes of Health, a Component of the US Dept. of Health & Human Services

Panacos Pharmaceuticals, Inc.

Hetero Labs Limited

Trimeris, Inc.

Other

University of North Carolina at Chapel Hill

Myrexis, Inc.

Dfh Therapeutics, Inc.

Niigata University of Pharmacy and Applied Life Sciences

Carl Thomas Wild

Dani Paul Bolognesi

Thomas James Matthews

Graham P Allaway

Theodore John Nitz

David Eugene Martin

Dennis Michael Lambert

Stephen Robert Petteway

Shawn O'Lin Barney

Parthasaradhi Reddy Bandi

Rathnakar Reddy Kura

Panduranga Reddy Adulla

Eric O Freed

David Krupadanam Gazula Levi

Alphonse J Langlois

Bhaskar Reddy Kasireddy

Feng Li

Eswara Rao Bammidi

Karl Salzwedel

Thomas J Matthews

Kuo-Hsiung Lee

Lan Xie

David E Martin

Yoshiki Kashiwada

Ranga Reddy

Carol D Weiss

Sudhakar Neela

Shawn O'lin Barney

Stephen R Petteway

The present invention concerns novel pharmaceutically active triterpene amine derivatives, pharmaceutical compositions containing the same, their use as medicaments, and the use of the compounds for the manufacture of specific medicaments. The present invention also concerns a method of treatment involving administration of the triterpene amine compounds. Specifically, the compounds are derivatives of betulinic acid having substitutions at one or more of the C-3, C-28 and C-19 positions as further described herein. The novel compounds are useful as antiretroviral agents. In particular, the novel compounds are useful for the treatment of Human Immunodeficiency Virus-1 (HIV-1).

Triterpene amine derivatives

The present invention relates to C-3 novel triterpenone with C-28 urea derivatives of formula (I); or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R, R, R, W, J and X are as defined herein. The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) useful for the treatment of viral diseases and particularly HIV mediated diseases. 

C-3 novel triterpenone with C-28 urea derivatives as HIV inhibitors

The invention relates to C-3 novel triterpenone with C-28 amide derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases (formula 1). 

C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors

The present invention relates to novel betulinic proline imidazole derivatives and related compounds, compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases. 

Betulinic proline imidazole derivatives as HIV inhibitors

Inhibition of HIV-1 replication by disrupting the processing of the viral Gag capsid (CA) protein (p24) from the CA-spacer peptide 1 (SP1) protein precursor (p25) is disclosed. Amino acid sequences containing a mutation in the Gag p25 protein, with the mutation resulting in a decrease in the inhibition of processing of p25 to p24 by dimethylsuccinyl betulinic acid or dimethylsuccinyl betulin, polynucleotides encoding such mutated sequences and antibodies that selectively bind such mutated sequences are also included. Methods of inhibiting, inhibitory compounds and methods of discovering inhibitory compounds that target proteolytic processing of the HIV Gag protein are included. In one embodiment, such compounds inhibit the interaction of the HIV protease enzyme with Gag by binding to the Gag proteolytic cleavage site rather than to the protease enzyme. In another embodiment, viruses or recombinant proteins that contain mutations in the region of the Gag proteolytic cleavage site can be used in screening assays to identify compounds that target proteolytic processing.

Inhibition of HIV-1 replication by disruption of the processing of the viral capsid-spacer peptide 1 protein

Inhibition of HIV-1 replication by disrupting the processing of the viral Gag capsid (CA) protein (p24) from the CA-spacer peptide 1 (SP1) protein precursor (p25) is disclosed. Amino acid sequences containing a mutation in the Gag p25 protein, with the mutation resulting in a decrease in the inhibition of processing of p25 to p24 by dimethylsuccinyl betulinic acid or dimethylsuccinyl betulin, polynucleotides encoding such mutated sequences and antibodies that selectively bind such mutated sequences are also included. Methods of inhibiting, inhibitory compounds and methods of discovering inhibitory compounds that target proteolytic processing of the HIV Gag protein are included. In one embodiment, such compounds inhibit the interaction of the HIV protease enzyme with Gag by binding to Gag rather than to the protease enzyme. In another embodiment, viruses or recombinant proteins that contain mutations in the region of the Gag proteolytic cleavage site can be used in screening assays to identify compounds that target proteolytic processing.

Betulin and dihydrobetulin acyl derivatives according to the present invention have been found to have potent anti-HIV activity. The compounds of the present invention have Formula I as described herein, or pharmaceutically acceptable salts thereof; wherein Ris a C-Csubstituted or unsubstituted carboxyacyl or ester thereof; Ris hydrogen, halogen, hydroxyl or &#x2014;OR, Ris C-Csubstituted or unsubstituted carboxyacyl; and Ris hydrogen or C(CH); wherein the dashed line represents an optional double bond between C20 and C29.

Monoacylated betulin and dihydrobetulin derivatives, preparation thereof and use thereof

The present invention is directed to the induction and characterization of a humoral immune response targeting 'entry-relevant' gp41 structures. In its broadest aspect, the present invention is directed to methods of raising a neutralizing antibody response to a broad spectrum of HIV strains and isolates. The present invention targets particular molecular conformations or structures that occur at the cell surface of HIV during viral entry into host cells. Such a humoral response can be generated in vivo as a prophylactic measure in individuals to reduce or inhibit the ability of HIV to infect uninfected cells in the individual's body. Such a response can also be employed to raise antibodies against 'entry relevant' gp41 structures. These antibodies can be employed for therapeutic uses, and as tools for further illuminating the mechanism of HIV cell entry.

Methods of eliciting broadly neutralizing antibodies targeting HIV-1 gp41

The present invention relates to peptides which exhibit potent anti-retroviral activity. The peptides of the invention comprise DP178 (SEQ ID:1) peptide corresponding to amino acids 638 to 673 of the HIV-1gp41 protein, and fragments, analogs and homologs of DP178. The invention further relates to the uses of such peptides as inhibitory of human and non-human retroviral, especially HIV, transmission to uninfected cells.

Nucleic acids encoding DP-178 and other viral fusion inhibitor peptides useful for treating aids

Fusion proteins comprising DP-178 and other viral fusion inhibitor peptides useful for treating aids

The present invention relates to peptides which exhibit potent anti-retroviral activity. The peptides of the invention comprise DP178 (SEQ ID:1) peptide corresponding to amino acids 638 to 673 of the HIV-1 gp41 protein, and fragments, analogs and homologs of DP178. The invention further relates to the uses of such peptides as inhibitory of human and non-human retroviral, especially HIV, transmission to uninfected cells.

Methods for inhibition of membrane fusion-associated events, including HIV transmission

Substituted 3&prime;,4&prime;-di-O-camphanoyl-(&plus;)-cis-khellactone analogs, compositions thereof, and methods for using thereof

The invention is directed to a methods for identifying compounds that inhibit or prevent infection of cells by enveloped viruses such as HIV-1 by preventing or disrupting conformational changes in the viral transmembrane protein that are required for virus fusion with those cells, and the compounds discovered by such methods. The invention also includes using these assays as diagnostic assays to detect antibodies in virus infected individuals that inhibit the viral entry processes.

Assay for detection of viral fusion inhibitors

This invention relates to human immunodeficiency virus (HIV) protein fragments which have antiviral activity, and particularly relates to HIV peptides derived from the HIV transmembrane glycoprotein (gp41) which inhibit HIV-induced cell-cell fusion. This invention further relates to methods for the inhibition of enveloped viral infection, and to methods that modulate biochemical processes which involve coiled coil peptide interactions.

Compounds which inhibit HIV replication

The present invention relates to peptides which exhibit potent anti-viral activity. In particular, the invention relates to methods of using such peptides as inhibitory of respiratory syncytial virus (&ldquo;RSV&rdquo;) transmission to uninfected cells. The peptides used in the methods of the invention are homologs of the DP-178 and DP-107 peptides, peptides corresponding to amino acid residues 638 to 673, and to amino acid residues 558 to 595, respectively, of the HIV-1 transmembrane protein (TM) gp41.

Methods for inhibition of membrane fusion-associated events, including respiratory syncytial virus transmission

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Gaithersburg, MD, United States of America

Carl Thomas Wild