High Through-Put Screening of Small Molecules to Treat Drug Resistant HIV

DESCRIPTION (provided by applicant): Nearly 40 million people worldwide were living with HIV/AIDS in 2006. Approximately 40,000 people in the United States were newly diagnosed with HIV in 2005. HIV, a fast-replicating lentivirus, with many mutations is ex tremely difficult to treat. Between 10% and 30% of all patients carry at least one HIV strain that is resistant to at least one of the current HIV therapies. Given that all wild type and mutant HIV strains use the same human tRNA for replication, Cognosci has developed a high through-put screening system (HTS) that cost-effectively replicates in vitro the interaction of HIV proteins with this human tRNA that is critical for HIV viral replication. The overall goal of this Phase I SBIR project is to optimize Cognosci's novel screening technology and to prove the feasibility of screening for small molecules that interfere with this biological function essential for viral replication. The initial Specific Aim is for Cognosci to complete a selection of binding pe ptides that best emulate the HIV protein-human tRNA interaction and to standardize the HTS assay. Aims 2-4 are focused on demonstrating three levels of screening to identify small-molecules that inhibit this interaction. Up to 1000 compounds at high concen tration will be analyzed in Cognosci's HIV HTS. The 200 compounds selected in the first screen will be tested for their dose-dependent inhibitory activities. The 50 compounds with the lowest inhibitory concentrations will be further reduced on the basis of specificity for the HIV protein-tRNA interaction. By targeting HIV's recruitment of human tRNA, HIV therapeutics can be identified that greatly limit or even eliminate HIV's ability to develop resistance. This will allow us to provide much better treatmen t options for HIV patients both with and without drug-resistant HIV, and will protect the public at large by better managing the HIV pandemic. PUBLIC HEALTH RELEVANCE: Between 10% and 30% of HIV patients carry at least one drug-resistant strain of HIV. New HIV therapeutics are needed to provide better treatment options for HIV patients with and without drug resistance and to protect the public at large by better managing the worldwide HIV epidemic. The overall goal of this SBIR project is to optimiz e and then demonstrate the feasibility of Cognosci's high through-put screening (HTS) technology by cost-effectively screening small molecules that interfere with HIV protein recruitment of human tRNA, potentially resulting in an HIV therapeutic that is mo re difficult, if not impossible, for the HIV virus to develop drug resistance.