Entry of the human immunodeficiency virus type-1 (HIV-1) into the target cell is initiated by binding of the envelope glycoprotein surface unit gp120 to CD4 and a coreceptor (CXCR4 or CCR5) followed by gp41 refolding from its native conformation to a fusion-active conformation, a six-helix bundle consisting of three pairs of the N- and C-terminal heptad repeats (NHR and CHR, respectively). This refolding process brings the viral and target cell membranes together for fusion. Peptides derived from CHR region, named C- peptides, are able to bind to the gp41 NHR region to block formation of the fusion-active gp41 core, thereby inhibiting gp41-mediated membrane fusion. We previously hypothesized that a small molecule that binds to the gp41 NHR, especially the cavity region, may block the gp41 six-helix bundle formation and inhibit HIV-1 fusion. This hypothesis was validated by identification of several non-peptidic HIV-1 fusion inhibitors with """"""""drug-like"""""""" properties, e.g., NB-2 and NB-64, which block the fusion-active gp41 core formation. Most recently, we identified a series of small molecule compounds with structures similar to NB-2 and NB-64, but having much improved anti-HIV-1 activity. Some of these compounds, e.g., NB-154 and NB- 206 have IC50 (concentration for 50% inhibition of HIV-1 infection) values are in nanomolar range. These compounds effectively inhibited HIV-1 fusion and replication by targeting gp41 and may serve as leads for developing novel anti-HIV-1 therapeutics. We hypothesize that more potent small molecule HIV-1fusion inhibitors as anti-HIV-1 drug candidates can be designed based on the structures of NB-154 and NB- 206 by lead optimization.
The specific aims of this project are: 1) to establish a focused chemical library based on the structures of the lead compounds NB-154 and NB-206;2) To determine the structure-activity relationship (SAR) for lead optimization and for designing more potent anti-HIV-1 compounds;3) to study the mechanism of action of the most active HIV-1 fusion inhibitors;and 4) to evaluate the efficacy of the selected compounds on in vitro infection by cell-free and cell-associated primary HIV-1 strains with distinct genotypes and phenotypes. The long-term goal is to develop novel small molecule HIV-1 fusion inhibitors asa new class of anti-HIV-1 drugs. Since more than 40 million people in the world are living with HIV/AIDS, development of new anti-HIV drugs is urgently needed for treatment of patents with HIV infection/AIDS, especially for those who fail to respond to the current antiretroviral drugs. Therefore, this research is relevant to public health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Discovery and Development of Therapeutics Study Section (ADDT)
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Turk, Steven R
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New York Blood Center
New York
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