EVALUATION OF SELECTED CHEMOTYPES IN COUPLED CELLULAR AND MOLECULAR TARGET-BASED SCREENS IDENTIFIES NOVEL HIV-1 ZINC-FINGER INHIBITORS

Conservation of the Cys-Xaa(2)-Cys-Xaa(4)-His-Xaa(4)-Cys retroviral zi nc finger sequences and their absolute requirement in both the early a nd late phases of retroviral replication make these chemically reactiv e structures prime antiviral targets. We recently reported that select 2,2'-dithiobisbenzamides (DIBAs) chemically modify the zinc finger Cy s residues, resulting in release of zinc from the fingers and inhibiti on of HIV replication. In the current study we surveyed 21 categories of disulfide-based compounds from the chemical repository of the Natio nal Cancer Institute for their capacity to act as retroviral zinc fing er inhibitors. Aromatic disulfides that exerted anti-HIV activity tend ed to cluster in the substituted aminobenzene, benzoate, and benzenesu lfonamide disulfide subclasses. Only one thiuram derivative exerted mo derate anti-HIV activity, while a number of nonaromatic thiosulfones a nd miscellaneous disulfide congeners were moderately antiviral. Two co mpounds (NSC 20625 and NSC 4493) demonstrated anti-HIV activity in pro liferating T cell cultures and in nonproliferating monocyte/macrophage cultures. The two compounds chemically modified the p7NC zinc fingers in two separate in vitro assays, and interatomic surface molecular mo deling docked the compounds efficiently but differentially into the zi nc finger domains. The combined efforts of rational drug selection, ce ll-based screening, and molecular target-based screening led to the id entification of zinc finger inhibitors that can now be optimized by me dicinal chemistry for the development of biopharmaceutically useful an ti-HIV agents.