PA-457: a Potent HIV Inhibitor That Disrupts Core Condensation by Targeting a Late Step in Gag Processing

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Oct 24

PMID 14573704

Citations 201

Authors

F Li

R Goila-Gaur

K Salzwedel

N R Kilgore

M Reddick

C Matallana

A Castillo

D Zoumplis

D E Martin

J M Orenstein

G P Allaway

E O Freed

C T Wild

Affiliations

Soon will be listed here.

Abstract

New HIV therapies are urgently needed to address the growing problem of drug resistance. In this article, we characterize the anti-HIV drug candidate 3-O-(3',3'-dimethylsuccinyl) betulinic acid (PA-457). We show that PA-457 potently inhibits replication of both 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). We 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 we selected for PA-457-resistant virus in vitro. Consistent with the effect on Gag processing, we found that mutations conferring resistance to PA-457 map to the p25 to p24 cleavage site. 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.

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