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Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein

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 fr...

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Autores principales: Vozzolo, Luciano, Loh, Belinda, Gane, Paul J., Tribak, Maryame, Zhou, Lihong, Anderson, Ian, Nyakatura, Elisabeth, Jenner, Richard G., Selwood, David, Fassati, Ariberto
Formato: Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998086/
https://www.ncbi.nlm.nih.gov/pubmed/20937817
http://dx.doi.org/10.1074/jbc.M110.155275
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author Vozzolo, Luciano
Loh, Belinda
Gane, Paul J.
Tribak, Maryame
Zhou, Lihong
Anderson, Ian
Nyakatura, Elisabeth
Jenner, Richard G.
Selwood, David
Fassati, Ariberto
author_facet Vozzolo, Luciano
Loh, Belinda
Gane, Paul J.
Tribak, Maryame
Zhou, Lihong
Anderson, Ian
Nyakatura, Elisabeth
Jenner, Richard G.
Selwood, David
Fassati, Ariberto
author_sort Vozzolo, Luciano
collection PubMed
description 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.
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spelling pubmed-29980862011-01-04 Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein Vozzolo, Luciano Loh, Belinda Gane, Paul J. Tribak, Maryame Zhou, Lihong Anderson, Ian Nyakatura, Elisabeth Jenner, Richard G. Selwood, David Fassati, Ariberto J Biol Chem Microbiology 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. American Society for Biochemistry and Molecular Biology 2010-12-10 2010-10-11 /pmc/articles/PMC2998086/ /pubmed/20937817 http://dx.doi.org/10.1074/jbc.M110.155275 Text en © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles
spellingShingle Microbiology
Vozzolo, Luciano
Loh, Belinda
Gane, Paul J.
Tribak, Maryame
Zhou, Lihong
Anderson, Ian
Nyakatura, Elisabeth
Jenner, Richard G.
Selwood, David
Fassati, Ariberto
Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein
title Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein
title_full Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein
title_fullStr Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein
title_full_unstemmed Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein
title_short Gyrase B Inhibitor Impairs HIV-1 Replication by Targeting Hsp90 and the Capsid Protein
title_sort gyrase b inhibitor impairs hiv-1 replication by targeting hsp90 and the capsid protein
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998086/
https://www.ncbi.nlm.nih.gov/pubmed/20937817
http://dx.doi.org/10.1074/jbc.M110.155275
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