Grant: Doctoral Research Award - PA: Biomedical/Clinical HIV/AIDS Research

Although access to HAART has changed the prognosis of HIV infection to that of a chronic disease, the long term use of HAART is limited by issues of drug compliance, side effects and drug resistance. To respond to the continued need for new drugs, and in particular, those acting through as yet unexplored mechanisms of action, my PhD thesis research is directed toward the development small molecule inhibitors of HIV alternative splicing as a new therapy for HIV/AIDS. This project began with the discovery of the tetracyclic indole compound IDC16, the first small molecule known to inhibit the exonic splicing enhancer activity of SRSF1. The splicing factor SRSF1 plays a crucial, but 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 Tat and Rev. These RNA-binding proteins are key 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. The advantages of blocking SRSF1 as an anti HIV/AIDS strategy over the use of existing drugs are that: (i) this protein is essential for HIV replication, and (ii) targeting a human protein decreases the chances of mutations and subsequent resistance to drug therapy. Our laboratories effort to design new ring opened mimics of IDC16 has led to identification of several di(hetero)arylamide (DHA) type compounds that block the replication of HIV at concentrations comparable to AZT. Unlike IDC16 these new molecules are not inherently cytotoxic. My PhD thesis research is focused on optimizing the activity/selectivity and in vivo properties of these active molecules. The development of this new class of anti-HIV/AIDS drug with minimal risk of resistance will potentially have considerable impact on the quality of life of HIV/AIDS victims, and will have considerable social/financial impact on Canadian society.