Novel Phenanthrene and Anthracene Diketo Acids as Integrase Inhibitors For HIV Therapy
Health Sciences Technologies for Licensing
Current generation anti-HIV retroviral drugs fall into two categories, reverse transcriptase inhibitors or protease inhibitors. Although combination therapies using existing drugs have provided tremendous clinical benefits, drug resistance can and does develop, and there is a constant need for new therapeutics. In addition to new molecules that inhibit the two proven targets, many scientists are trying to develop drugs that target other HIV proteins. The HIV integrase protein, which catalyzes the integration of viral DNA into the host cell genome, is one of the targets being investigated for the next generation of antiretroviral drugs.
Researchers at the University of Tennessee have identified phenanthrene and anthracene diketo acids that bind to and inhibit the HIV integrase protein. Novel compounds exhibited a sub-micromolar IC50 in inhibiting integrase activity. One inhibitor, 2,4-dioxo-4-phenanthren-9-yl-butyric acid, had an IC50 of 0.38 μM against integrase strand transfer. Some of the potent compounds inhibited HIV-1 replication in human peripheral blood mononuclear cells (PBMC) with EC50 down to 8 μM with a selectivity index of 10 against PBMCs. The researchers continue to refine and screen new compounds using computational modeling and binding simulations, and expect to develop even more effective compounds.
- There is a general selectivity against the integrase strand transfer step
- Low cytotoxicity during in vitro studies
- US 200900884444