PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing
| Autor: | Carl T. Wild, Graham P. Allaway, A. Castillo, C. Matallana, Ritu Goila-Gaur, Jan M. Orenstein, Dorian Zoumplis, Mary Reddick, David E. Martin, Karl Salzwedel, Nicole Kilgore, Eric O. Freed, Feng Li |
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| Rok vydání: | 2003 |
| Předmět: |
Genotype
Anti-HIV Agents viruses HIV Core Protein p24 Gene Products gag Biology gag Gene Products Human Immunodeficiency Virus Virus Inhibitory Concentration 50 chemistry.chemical_compound Humans Binding site Binding Sites Multidisciplinary Models Genetic Maturation inhibitor Drug discovery Succinates Biological Sciences Viral membrane Precipitin Tests Virology Triterpenes In vitro Microscopy Electron Models Chemical Capsid chemistry Chromobox Protein Homolog 5 Drug Design Mutation Bevirimat HeLa Cells Plasmids |
| Zdroj: | Proceedings of the National Academy of Sciences. 100:13555-13560 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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