Grant: Operating Grant - PA: HIV/AIDS Research Initiative - Biomedical/Clinical Stream

An estimated 33 million people live with HIV/AIDS. Although access to Highly Active Anti-Retroviral Therapy (HAART) has dramatically changed the prognosis of HIV infection, issues of drug compliance, resistance and side effects necessitiates the constant need for new drugs. This project defines the objectives and milestones of our continuing research to develop small molecule inhibitors of alternative splicing as a new therapy for HIV/AIDS. Key regulators of alternative splicing are a family of SR proteins, which include SRSF1. This SR protein plays a generally redundant role in human RNA splicing. However, in HIV-1 infected cells it specifically regulates alternative splicing events that are vital to the production of critical HIV proteins that are regulators for the expression of HIV-1 viral genes, for the synthesis of full-length genomic RNA and, ultimately, for the production of progeny virions. An important advantage to blocking SRSF1 as an anti HIV/AIDS strategy is that targeting a human protein decreases the chances of mutations and subsequent resistance to drug therapy. Our research has focused on the design of ring-opened non cytotoxic mimics of the SRSF1 inhibitor IDC16. This has led to the identification of 4 novel di(hetero)arylamide (DHA) type compounds that display activity comparable to AZT. This result forms the basis for the research outlined in our proposal, whose ultimate objective is to develop a new anti-HIV/AIDS drug.