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      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 of the United States of America

      Drug Design, gag Gene Products, Human Immunodeficiency Virus, pharmacology, chemistry, Triterpenes, Succinates, Precipitin Tests, metabolism, Plasmids, Mutation, Models, Genetic, Models, Chemical, Microscopy, Electron, Inhibitory Concentration 50, Humans, HeLa Cells, HIV Core Protein p24, Genotype, antagonists & inhibitors, Gene Products, gag, Binding Sites, Anti-HIV Agents

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          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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          Author and article information

          Journal
          14573704
          263852
          10.1073/pnas.2234683100

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