Progenics Pharmaceuticals, Inc.

Panacos Pharmaceuticals, Inc.

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

Other

University of North Carolina at Chapel Hill

Myrexis, Inc.

Niigata University of Pharmacy and Applied Life Sciences

Graham P Allaway

Paul J Maddon

Virginia M Litwin

Carl Thomas Wild

William C Olson

Eric O Freed

Feng Li

Karl Salzwedel

Kuo-Hsiung Lee

Lan Xie

Yoshiki Kashiwada

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

This invention provides methods for inhibiting fusion of HIV-1 to CD4cells which comprise contacting CD4cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4cells which comprise contacting CD4cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4cells effective to prevent fusion of HIV-1 to CD4cells and a pharmaceutically acceptable carrier.

CCR5 chemokine receptor-specific monoclonal antibodies capable of inhibiting HIV-1 cell fusion

This invention provides: agents determined to be capable of specifically inhibiting the fusion of a macrophage-tropic primary isolate of HIV-1 to a CD4cell, but not a T cell-tropic isolate of HIV-1 to a CD4cell; and agents determined to be capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 to a CD4cell, but not a macrophage-tropic primary isolate of HIV-1 to a CD4+ cell. This invention also provides: agents capable of specifically inhibiting the fusion of a macrophage tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1; and agents capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1. The agents include but are not limited to antibodies. This invention further provides: methods of inhibiting fusion of a macrophage-tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion; and methods of inhibiting fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion.

Methods for assaying inhibition of HIV-1 envelope glycoprotein-mediated membrane fusion

This invention provides agents determined to be capable of inhibiting the fusion of a macrophage-tropic primary isolate of HIV-1 to a CD4cell and agents determined to be capable of inhibiting the fusion of a T cell-tropic isolate of HIV-1 to a CD4cell. This invention also provides methods to identify such agents. This invention further provides methods of inhibiting fusion of a macrophage-tropic primary isolate of HIV-1 with a CD+ cell and methods of inhibiting fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1.

Methods for inhibiting HIV-1 envelope glycoprotein-medicated membrane fusion

Methods of inhibiting human immunodeficiency virus type 1 (HIV-1) infection through the administration of CCR5 chemokine receptor antagonists

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

This invention provides an antibody capable of specifically inhibiting the fusion of an HIV-1 envelope glycoproteincell with an appropriate CD4cell without cross reacting with the HIV-1 envelope glycoprotein or CD4 and capable of inhibiting infection by one or more strains of HIV-1. This antibody is then used to identify a molecule which is important for HIV infection. Different uses of the antibody and the molecule are described.

Compounds capable of inhibiting HIV-1 infection

Methods for inhibiting HIV-1 infection

This invention provides: agents determined to be capable of specifically inhibiting the fusion of a macrophage-tropic primary isolate of HIV-1 to a CD4cell, but not a T cell-tropic isolate of HIV-1 to a CD4cell; and agents determined to be capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 to a CD4cell, but not a macrophage-tropic primary isolate of HIV-1 to a CD4cell. This invention also provides: agents capable of specifically inhibiting the fusion of a macrophage tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1; and agents capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1. The agents include but are not limited to antibodies. This invention further provides: methods of inhibiting fusion of a macrophage-tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion; and methods of inhibiting fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion.

Methods for using resonance energy transfer-based assay of HIV-1 envelope glycoprotein-mediated membrane fusion, and kits for practicing same

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

This invention provides an immunoconjugate which comprises 1) a non-peptidyl toxin and 2) a CD4-gamma2 chimeric heavy chain homodimer linked thereto. This invention also provides an immunoconjugate which comprises 1) a gamma radiation-emitting radionuclide of low to moderate cytotoxicity and 2) a CD4-gamma2 chimeric heavy chain homodimer linked thereto. This invention further provides an immunoconjugate which comprises 1) a non-peptidyl toxin and 2) a heterotetramer comprising two heavy chains and two light chains, both heavy chains being either a) IgG2 heavy chains or b) chimeric CD4-IgG2 heavy chains, and both light chains being either a) kappa light chains or b) chimeric CD4-kappa light chains. This invention further provides an immunoconjugate which comprises 1) a gamma radiation-emitting radionuclide of low to moderate cytotoxicity and 2) a heterotetramer comprising two heavy chains and two light chains, both heavy chains being either a) IgG2 heavy chains or b) chimeric CD4-IgG2 heavy chains, and both light chains being either a) kappa light chains or b) chimeric CD4-kappa light chains. Finally, this invention provides methods of using the immunoconjugates of the subject invention.

Non-peptidyl moiety-conjugated CD4-gamma2 and CD4-IgG2 immunoconjugates, and uses 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 provides methods for inhibiting fusion of HIV-1 to CD4 cells which comprise contacting CD cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4 cells which comprise contacting CD4 cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 cells effective to prevent fusion of HIV-1 to CD4 cells and a pharmaceutically acceptable carrier.

Method for preventing HIV-1 infection of CD4&plus; cells

This invention provides an immunoconjugate which comprises 1) a non-peptidyl toxin and 2) a CD4-gamma2 chimeric heavy chain homodimer linked thereto. This invention also provides an immunoconjugate which comprises 1) a gamma radiation-emitting radionuclide of low to moderate cytotoxicity and 2) a CD4-gamma2 chimeric heavy chain homodimer linked thereto. This invention further provides an immunoconjugate which comprises 1) a non-peptidyl toxin and 2) a heterotetramer comprising two heavy chains and two light chains, both heavy chains being either 1) IgG2 heavy chains or b) chimeric CD4-IgG2 heavy chains, and both light chains being either a) kappa light chains or b) chimeric CD4-kappa light chains. This invention further provides an immunoconjugate which comprises 1) a gamma radiation-emitting radionuclide of low to moderate cytotoxicity and 2) a heterotetramer comprising two heavy chains and two light chains, both heavy chains being either a) IgG2 heavy chains or b) chimeric CD4-IgG2 heavy chains, and both light chains being either a) kappa light chains or b) chimeric CD4-kappa light chains. Finally, this invention provides methods of using the immunoconjugates of the subject invention.

Growing community of inventors

Darnestown, MD, United States of America

Graham P Allaway