NIH Research Festival
Although antiretroviral therapy to treat HIV has advanced, there remains a critical need for new therapeutics, especially those targeted at resistant viral strains. The Gag polyprotein, and in particular its constituent nucleocapsid protein, NC, represents a prime target for antiretroviral inhibition. Comprised of two highly-conserved zinc fingers, NC plays multiple roles throughout the virus replication cycle. A novel class of NC inhibitors, based upon an S-acyl-2-mercaptobenzamide thioester (SAMT) scaffold, promotes zinc ejection from NC. These compounds display potent antiviral activity without evidence of cytotoxicity in cell models, ex vivo cervical explants, and in animal models. Using mass spectrometry approaches, we have examined the mechanism of Gag inactivation both in vitro and in treated cells. We have identified a novel mechanism of action for this class of inhibitors that involves covalent modification of Gag, both within and outside NC.
Scientific Focus Area: Virology
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