PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing.
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.
Li
F
F
Panacos Pharmaceuticals Inc., 209 Perry Parkway, Gaithersburg, MD 20877, USA.
Goila-Gaur
R
R
Salzwedel
K
K
Kilgore
N R
NR
Reddick
M
M
Matallana
C
C
Castillo
A
A
Zoumplis
D
D
Martin
D E
DE
Orenstein
J M
JM
Allaway
G P
GP
Freed
E O
EO
Wild
C T
CT
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001665:Binding Sites; D000090266:Chromobox Protein Homolog 5; D015195:Drug Design; D015683:Gene Products, gag / Q000037:antagonists & inhibitors / Q000737:chemistry*; D005838:Genotype; D016655:HIV Core Protein p24 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008854:Microscopy, Electron; D008956:Models, Chemical; D008957:Models, Genetic; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D013386:Succinates / Q000737:chemistry / Q000494:pharmacology*; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D054301:gag Gene Products, Human Immunodeficiency Virus; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D000090266:Chromobox Protein Homolog 5; D015683:Gene Products, gag; D016655:HIV Core Protein p24; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C000715594:CBX5 protein, human; C059827:HIV gag protein p25; C479935:bevirimat; D053978:Pentacyclic Triterpenes