Dan Appella, NIH
Faculty host: Prof. Hoover
Simple mercaptobenzamide derivatives inactivate the nucleocapsid protein, NCp7, of
HIV-1 via a unique mechanism of intracellular acetylation. The protein NCp7 is a
small protein that contains 55 amino acids and consists of two zinc-finger motifs
that bind to oligonucleotides. 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 render the virus non-infectious. Therefore, disruption
of NCp7 is an effective strategy to prevent HIV maturation and represents a unique
strategy for drug development. Treatment of HIV- infected white blood cells with
specific mercaptobenzamide 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 mercaptobenzamide 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. 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.
