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 K. Nyakatura, Richard G. Jenner, David Selwood, Ariberto Fassati

Research output: Contribution to journalArticle

44 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Capsid Proteins
HIV-1
Gene expression
Gene Expression
Viral Genes
Cyclophilin A
Host-Pathogen Interactions
Dimerization
Chromatin Immunoprecipitation
Capsid
Pathogens
coumermycin
Viruses
Point Mutation
Dimers
Chromatin
Adenosine Triphosphate
Cells
Molecules
DNA

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Vozzolo, L., Loh, B., Gane, P. J., Tribak, M., Zhou, L., Anderson, I., ... 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

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 K.; Jenner, Richard G.; Selwood, David; Fassati, Ariberto.

In: Journal of Biological Chemistry, Vol. 285, No. 50, 10.12.2010, p. 39314-39328.

Research output: Contribution to journalArticle

Vozzolo, L, Loh, B, Gane, PJ, Tribak, M, Zhou, L, Anderson, I, Nyakatura, EK, Jenner, RG, Selwood, D & Fassati, A 2010, 'Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein', Journal of Biological Chemistry, vol. 285, no. 50, pp. 39314-39328. https://doi.org/10.1074/jbc.M110.155275
Vozzolo, Luciano ; Loh, Belinda ; Gane, Paul J. ; Tribak, Maryame ; Zhou, Lihong ; Anderson, Ian ; Nyakatura, Elisabeth K. ; Jenner, Richard G. ; Selwood, David ; Fassati, Ariberto. / Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 50. pp. 39314-39328.
@article{7d79ea1075334d509ebdf97b4baf8505,
title = "Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein",
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.",
author = "Luciano Vozzolo and Belinda Loh and Gane, {Paul J.} and Maryame Tribak and Lihong Zhou and Ian Anderson and Nyakatura, {Elisabeth K.} and Jenner, {Richard G.} and David Selwood and Ariberto Fassati",
year = "2010",
month = "12",
day = "10",
doi = "10.1074/jbc.M110.155275",
language = "English (US)",
volume = "285",
pages = "39314--39328",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "50",

}

TY - JOUR

T1 - Gyrase B inhibitor impairs HIV-1 replication by targeting Hsp90 and the capsid protein

AU - Vozzolo, Luciano

AU - Loh, Belinda

AU - Gane, Paul J.

AU - Tribak, Maryame

AU - Zhou, Lihong

AU - Anderson, Ian

AU - Nyakatura, Elisabeth K.

AU - Jenner, Richard G.

AU - Selwood, David

AU - Fassati, Ariberto

PY - 2010/12/10

Y1 - 2010/12/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78649867001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649867001&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.155275

DO - 10.1074/jbc.M110.155275

M3 - Article

C2 - 20937817

AN - SCOPUS:78649867001

VL - 285

SP - 39314

EP - 39328

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 50

ER -