Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein

Luciano Vozzolo, Belinda Loh, Paul J. Gane, Maryame Tribak, Lihong Zhou, Ian Anderson, Elisabeth Nyakatura, Richard G. Jenner, David Selwood, Ariberto Fassati

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Chemical genetics is an emerging approach to investigate the biology of host-pathogen interactions. We screened several inhibitors of ATP-dependent DNA motors and detected the gyrase B inhibitor coumermycin A1 (C-A1) as a potent antiretroviral. C-A1 inhibited HIV-1 integration and gene expression from acutely infected cell, but the two activities mapped to distinct targets. Target discovery identified Hsp90 as the C-A1 target affecting viral gene expression. Chromatin immunoprecipitation revealed that Hsp90 associates with the viral promoter and may directly regulate gene expression. Molecular docking suggested that C-A1 binds to two novel pockets at the C terminal domain of Hsp90. C-A1 inhibited Hsp90 dimer formation, suggesting that it impairs viral gene expression by preventing Hsp90 dimerization at the C terminus. The inhibition of HIV-1 integration imposed by C-A1 was independent of Hsp90 and mapped to the capsid protein, and a point mutation at residue 105 made the virus resistant to this block. HIV-1 susceptibility to the integration block mediated by C-A1 was influenced by cyclophilin A. Our chemical genetic approach revealed an unexpected function of capsid in HIV-1 integration and provided evidence for a role of Hsp90 in regulating gene expression in mammalian cells. Both activities were amenable to inhibition by small molecules and represent novel antiretroviral drug targets.

Original languageEnglish (US)
Pages (from-to)39314-39328
Number of pages15
JournalJournal of Biological Chemistry
Volume285
Issue number50
DOIs
StatePublished - Dec 10 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Vozzolo, L., Loh, B., Gane, P. J., Tribak, M., Zhou, L., Anderson, I., Nyakatura, E., Jenner, R. G., Selwood, D., & Fassati, A. (2010). Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein. Journal of Biological Chemistry, 285(50), 39314-39328. https://doi.org/10.1074/jbc.M110.155275