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Maturation
Inhibitor PA-457 Is a Potent Experimental Drug in a New Class of
Anti-HIV Compounds
New
HIV therapies are urgently needed to address the growing problem
of drug resistance. In this article, researchers at Panacos Pharmaceuticals
characterize the anti-HIV drug candidate 3-O-(3',3'-dimethylsuccinyl)
betulinic acid (PA-457).
The
investigators show that PA-457 potently inhibits replication of
both wild type (WT) WT and drug-resistant HIV-1 isolates and demonstrate
that the compound acts by disrupting a late step in Gag processing
involving conversion of the capsid precursor (p25) to mature capsid
protein (p24).
The
researchers find that virions from PA-457-treated cultures are noninfectious
and exhibit an aberrant particle morphology characterized by a spherical,
acentric core and a crescent-shaped, electron-dense shell lying
just inside the viral membrane.
To
identify the determinants of compound activity they selected for
PA-457-resistant virus in vitro. Consistent with the effect on Gag
processing, the found that mutations conferring resistance to PA-457
map to the p25 to p24 cleavage site.
In
conclusion, the authors write, “PA-457 represents a unique class
of anti-HIV compounds termed maturation
inhibitors that exploit a previously unidentified
viral target, providing additional opportunities for HIV drug discovery.
Panacos
Pharmaceuticals Inc., 209 Perry Parkway, Gaithersburg, MD 20877,
USA.
12/06/04
Reference
F
Li and others. PA-457: a potent HIV inhibitor that disrupts
core condensation by targeting a late step in Gag processing. Proceedings of the National Academy
of Sciences 100(23): 13555-13560. November 11, 2003.
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