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J Biol Chem. 2010 Dec 10;285(50):39314-28. doi: 10.1074/jbc.M110.155275. Epub 2010 Oct 11.

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

Author information

1
Wohl Virion Centre, Division of Infection and Immunity, University College London, 46 Cleveland Street, W1T 4JF London, United Kingdom.

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.

PMID:
20937817
PMCID:
PMC2998086
DOI:
10.1074/jbc.M110.155275
[Indexed for MEDLINE]
Free PMC Article

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