The HIV-1 nucleocapsid protein, NCp7, is composed of two highly conserved zinc-binding domains and is important throughout the virus replication cycle. We have developed a class of small molecule inhibitors of NCp7, based upon an S-acyl-2-mercaptobenzamide thioester scaffold (SAMT). These compounds display antiviral activity without evidence of cytotoxicity. We investigated the mechanism of viral inactivation, demonstrating that SAMTs covalently modify NCp7 within the Gag polyprotein in treated cells. Moreover, we observed that the thiol released by reaction of the SAMT with NCp7/Gag is re-acetylated intracellularly to form an active thioester. Thus, a SAMT is able to be recycled, suggesting that a single molecule of SAMT could inhibit more than one molecule of NCp7/Gag. A direct consequence of the recycling mechanism is the development of pro-drugs that show improved stability while maintaining antiviral activity. We have systematically characterized different pro-drug molecules as to their activity and stability, identifying two lead molecules.

Inactivation of HIV-1 nucleocapsid NCp7 with a small molecule scaffold: In vitro mechanism and in vivo efficacy

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.