VIF anatagonist: lead Inhibitor Identification

Rana, Tariq

Abstract

According to the World Health Organization, 4.8 million people were newly infected with HIV in 2003bringing the total number to some 37.8 million people who are living with HIV. Since the first cases of AIDSwere identified in 1981, over 20 million have died by this disease. In spite of remarkable medical advances,HIV-1 infections continue to increase. Our goal is to identify drugs against a novel and unexploited targetfor the treatment of AIDS. The human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS,is a complex retrovirus that encodes six regulatory proteins, including Vif that is essential for viral replicationin vivo. Since there are no known cellular homologs of HIV-1 Vif, this protein represents an extremelyattractive, yet unrealized, target for antiviral intervention. Therefore, we propose to identify lead inhibitors ofHIV-1 Vif function.
Our specific aims are as follows: (1) Identification of Vif inhibitors. Experiments areproposed to develop highly robust and reproducible fluorescence-based assays to monitor HIV-1 Viffunction in cellular environment. High throughput screening assays will be employed to identify smallmolecule inhibitors that can target Vif-APOBEC3G interactions. (2) Structure activity relation studies andvalidation of lead compounds. Experiments are proposed to characterize the efficacy and specificity of thecompounds identified as Vif inhibitors from initial screening experiments. Selected compounds will be testedfor their anti-HIV Vif activities in both permissive and non-permissive cells (Project #2). Antiviral activities ofselected Vif antagonists against clinical HIV-1 isolates will be analyzed and the safety and stability profilesof these compounds will be determined (core B). Consequences of Vif antagonist's activities in chronicallyinfected macaques will be investigated in project #3. As a support to pharmacology studies (project #3 andcore B), we will measure the drug concentrations in plasma of drug treated animals. Based on the activity,stability, and toxicity data (projects 2 and 3, and core B), new compounds will be synthesized to improve thepotency and selectivity of lead structures. (3) Mechanism(s) of Vif inhibition. Experiments will be performedto understand the mechanism of Vif inhibitors at molecular level.