Rational Design of HIV Fusion Inhibitors Targeting gp41

New York Blood Center, New York NY

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Abstract

DESCRIPTION (provided by applicant): Entry of the human immunodeficiency virus type 1 (HIV-1) into the target cell is initiated by binding of the envelope glycoprotein surface unit gpl20 to CD4 and a coreceptor (CXCR4 or CCR5) followed by gp41 refolding from its native, metastable conformation to a final fusion-active, thermostable conformation. The latter conformation is 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, mimicking interactions in the six-helix bundle, 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 ADS-J1, a non-peptide HIV-1 fusion inhibitor which specifically binds to a "hot spot" in the gp41 NHR region that participates in formation of a hydrophobic cavity during gp41 refolding and blocks the fusion-active gp41 core formation. Most recently, we identified two novel N-substituted pyrrole derivatives with "drug-like" properties, designated NB-2 and NB-64. These two 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-1 fusion inhibitors as anti-HIV-1 drug candidates can be designed based on the structures of NB-2 and NB-64 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-2 and NB-64; 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 as a new class of anti-HIV-1 drugs.