The RCMI Program in Health Disparities Research at Meharry Medical College (Supplement)

Meharry Medical College, Nashville TN

Investigators

Linked publications & trials

Abstract

AIDS disproportionately targets several minority groups, including the African American population. The burden is due to the high frequency of HIV-1 infection rates and the high incidence of virologic failure of HIV antiretroviral therapy, owing to the multidrug resistance in the African American population. To control the emergence of multidrug-resistant HIV-1 and solve the AIDS Health Disparities issue, it is important to develop drugs against novel viral targets. HIV-1 viral infectivity factor (Vif) is essential for virus replication. The primary function of Vif is to counteract APOBEC3G (A3G), a potent host restriction factor for HIV. Vif-A3G interaction has been the target for drug development. Accordingly, several groups have developed HTS assays to screen for small molecules to inhibit Vif-mediated A3G degradation. However, none have advanced to clinical trials due to their moderate potency in rescuing A3G antiviral function. Notably, there is evidence that Vif directly inhibits A3G cytidine deaminase activity (CDA). Given that the efforts to identify effective inhibitors of Vif-mediated A3G degradation have not been successful and A3G CDA is critical for its antiviral function, we will target Vif-mediated A3G CDA inhibition function for identifying novel Vif inhibitors. To develop a chemical probe and lay the foundation for discovering a new class of HIV drugs, we have established a novel and robust assay to screen small molecules that target this function of Vif with excellent reproducibility and a calculated Z-score of 0.83. In preliminary studies, we screened ~5500 compounds from a combination of several small compound libraries. We obtained one hit, Quinobene, which showed potent antiviral activity (IC50:0.75-1.25 μM) by restoring A3G function. The data validate our assay and support the hypothesis that screening a pharmacologically diverse small molecule library can lead to the identification of Vif-specific inhibitors that target A3G CDA activity. In this proposal, we propose to screen a collection of Natural Product Extracts (3K extracts, >30 compounds per extract, totaling ~10K chemicals) in collaboration with Dr. Ashu Tripathi, Director of the Natural Products Discovery Core at the University of Michigan (Aim 1). Natural Product Extracts (NPEs) with a high potency of inhibiting Vif function will be selected for further validating the potency of Vif inhibitors and perform secondary assays to verify their A3G-dependent anti-HIV activity in CD4+T cell lines (Aim 2). Finally, we will utilize the data-intensive platform of Tripathi's lab to rapidly de-convolute identified hits to characterize active leads and biologically characterize the promising leads in primary CD4+ T cells isolated from Caucasian and African American (AA) populations (Aim 3). The proposed experiments will (i) develop chemical probes that can be used to elucidate the function of Vif in counteracting A3G and (ii) lead to the discovery of potent anti-HIV inhibitors for the development of new class antiviral drugs to address multidrug resistance issue disproportionately targeting AA population.