ADVANCED GENETIC SYSTEMS, INC. — Department of Health and Human Services SBIR Phase I: DESCRIPTION (provided by applicant): There is a significant need for novel HIV therapies g

Description

DESCRIPTION (provided by applicant): There is a significant need for novel HIV therapies given the emergence of viruses resistant to existing drug regimens. The Rev-RRE protein-RNA interaction in HIV plays an essential role in the transport of viral mRNA from the nucleus to the cytoplasm where it can be translated or packaged. Previously we identified the thienopyridine scaffold that inhibited HIV replication and by targeting HIV Rev. We carried out extensive structure-activity (SAR) studies employing bothcommercial and synthesized analogs (gt 200 total) and identified the key structural elements necessary for activity (i.e., the essential pharmacophore). Iterative rounds of synthesis and testing in a robust panel of anti-HIV and toxicity assays, produced patentable new analogs that are 100-fold more potent than our original screening hits and with therapeutic indices gt4000, exceeding our original goals. Having successfully completed key milestones towards submission of an Investigational New Drug (IND), potential corporate partners have requested that we perform virology experiments to fully characterize the activity of the molecules with a diverse panel of viral isolates and cell types, and in combination with currently approved drugs. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: We previously carried out a structure-activity study of a promising Rev inhibitor and identified the key structural elements necessary for activity. We propose to carry out detailed virology studies to fully characterize the activity of the molecules with a diverse panel of viral isolates and cell types, and in combination with currently approved drugs.