Virology studies of a small molecule HIV Rev inhibitor

点击翻译按钮获取中文摘要

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 both commercial and synthesized analogs (> 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 >4000, 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.