Grant: Proof of Principle Program - Phase I

HIV/AIDS is treated as a "chronic infection" in developed countries, and aggressive measures are now being taken to bring Highly Active Anti-Retroviral Therapy (HAART or ART) to the developing world, where the majority of HIV infected people reside. Acutely important to the treatment of HIV infection in coming years is to address the inherent limitations to the ART strategy (necessity for strict adherence to treatment schedules, toxicity, and emergence of drug resistance). These issues take on added significance as the scale and diversity of the populations receiving treatment increases. There is a continued need for new drugs, acting through unexploited mechanisms of action that bypass resistance, have minimal toxicity, and address the problem of activating the latent viral pool. Our research in this field (CIHR operating grants 2009/2012) resulted in the discovery a small molecule inhibitor, "C-8", of HIV alternative splicing, and studies to evaluate its potential as an anti-HIV drug. Specifically, C8 is active against HIV strains resistant to the ART drugs; that minor perturbation of HIV pre-mRNA alternative splicing by C-8 is sufficient to block HIV replication; that C8 has minimal/no effect on the splicing of a panel of 100 cellular genes; that toxicity in cell based assays appears at concentrations much higher than the threshold for anti-HIV activity. A provisional patent was filed in April 2014. To progress our research toward commercialization, we request PoP1 fund to enable our team of 4 collaborating laboratories to expand the number of C8 analogues synthesized and to accelerate their evaluation as anti-HIV agents and alternative splicing inhibitors. The funding will further permit a more exhaustive study of drug-spliceosome target identification and in-depth toxicity/efficacy studies. As we are targeting a host factor it is imperative to demonstrate minimal/absence of toxicity to justify moving toward PoC animal studies.