The development of a new strategy to target the nucleocapsid protein of HIV-1, NCp7, using a unique class of small organic molecules will be presented. The protein NCp7 is a relatively small protein that contains 55 amino acids and consists of two zinc-finger motifs that bind to mRNA.  There are a number of regulatory roles for NCp7 in the HIV lifecycle, but the principle functions are to bind viral RNA, protect it from degradation, and facilitate packaging of genomic RNA into a new viral particle.  The zinc-fingers of NCp7 are highly conserved among HIV viral strains, and mutations of the zinc-finger motif renders the virus non-infectious.  Therefore, disruption of NCp7 is an effective strategy to prevent HIV replication and inhibit cell-to-cell transmission of the virus.  The small molecule, N-(3-amino-3-oxopropyl)-2-mercaptobenzamide, is highly effective at inactivating NCp7.  Treatment of HIV-infected white blood cells with this molecule or different prodrug derivatives results in crosslinking of NCp7, mis-processing of the gag polyprotein, and production of non-infectious virus particles.  These observations are consistent with a mechanism of action where the molecule promotes ejection of zinc from NCp7.  Another facet of this mechanism is that the molecule reacts intracellularly with acetyl CoA to form an acetyl thioester intermediate.  This S-acyl intermediate reacts directly with NCp7 to transfer an acetyl group to the protein, leading to zinc ejection, inactivation of NCp7, and regeneration of the original mercaptobenzamide molecule which can re-enter the acetyl CoA acylation pathway.  Therefore, N-(3-amino-3-oxopropyl)-2-mercaptobenzamide acts as a catalytic HIV inactivator where a single molecule has the potential to inhibit multiple NCp7 molecules.  In addition to presenting the mechanism of action, recent results on antiviral activity, formulation, and translation of prodrug derivatives to an orally bioavailable drug will be presented.

Targeting HIV nucleocapsid protein via a small molecule platform and related preclinical development

248th National Meeting (2014)

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