Institute for Cancer Research

Fox Chase Cancer Center

Hoffmann-la Roche Inc.

Anna Marie Skalka

Mark D Andrake

George W Merkel

Roger J Pomerantz

Gary D Kao

Ravi Shankar Bojja

Richard A Katz

Ellyn Fischberg-Bender

Rene Daniel

Diane Bizub

Giuseppe Nunnari

The disclosure generally relates to compounds, compositions, and methods for treating human immunodeficiency virus (HIV) infection. The disclosure provides novel inhibitors of HIV-1 integrase, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection.

Inhibitors of HIV-1 integrase multimerization

The disclosure generally relates to compounds of formulas (I) and (II)7 including compositions and methods for treating human immunodeficiency virus (HIV) infection. The disclosure provides novel inhibitors of HIV-1 integrase, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection.

Methods to inhibit the formation of retrovirus integrase reaching dimers, to dissociate retrovirus integrase reaching dimers, and to stabilize retrovirus integrase reaching dimers in a conformation in which retrovirus DNA-to host cell DNA integration activity of the integrase is inhibited are provided. Methods for treating a retrovirus infection, which target retrovirus integrase reaching dimer formation and/or stability are also provided.

Inhibition of human immunodeficiency virus integrase reaching dimer formation utilizing single-chain variable antibodies

Cellular targets for anti-retroviral drug development are disclosed. The cellular targets comprise ATR kinase and its relevant substrates, based on the identification of the ATR kinase as required for the final step of retroviral DNA integration. Assays for identifying modulators of retroviral integration via the ATR kinase pathway are disclosed, as well as modulators identified by such assays. Pharmaceutical preparations and methods of their use in treating retroviral infection are also disclosed.

Cellular targets for treatment of retroviral infection

The present invention provides novel chimeric and fusion proteins useful for facilitating site-specific integration of foreign DNA into a host genome. The chimeric enzymes of the invention comprise a DNA binding moiety fused to a retroviral integrase moiety, preferably at the precise N- or C-terminus. Nucleic acids encoding these fusion proteins can be incorporated into standard retroviral vectors, or can be provided as purified proteins. They are capable of exerting the activities of a wildtype retroviral integrase, including processing retroviral DNA termini, nicking double-stranded DNA and integrating a DNA molecule with processed retroviral termini into another DNA strand.

Chimeric enzyme for promoting targeted integration of foreign DNA into a

Preparation of novel polypeptide sequences spanning amino acid position 61 of the ras protein, said sequences being characterized as containing a leucine in that position instead of the glutamine found in normal ras protein, the utilization of such polypeptides to prepare immunogen compositions utilizing such polypeptide covalently linked to immunogenic carrier materials, the production of antibodies elicited by such polypeptides, the screening of such antibodies to provide monoclonals specific to the P21Tleu61 transforming protein and to immunoassay and use in immunochemical methods employing such antibodies to determine the presence of the p21TLeu61 transforming protein.

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Princeton, NJ, United States of America

Anna Marie Skalka