A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autoren

  • Dominic H. Banda
  • Paula M. Perin
  • Richard J.P. Brown
  • Daniel Todt
  • Wladimir Solodenko
  • Patrick Hoffmeyer
  • Kamlesh Kumar Sahu
  • Michael Houghton
  • Philip Meuleman
  • Rolf Müller
  • Andreas Kirschning
  • Thomas Pietschmann

Externe Organisationen

  • Ruhr-Universität Bochum
  • University of Alberta
  • Universiteit Gent
  • TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
  • Deutsches Zentrum für Infektionsforschung (DZIF)
  • Helmholtz-Institut für Pharmazeutische Forschung Saarland (HIPS)
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Details

OriginalspracheEnglisch
Seiten (von - bis)1082-1092
Seitenumfang11
FachzeitschriftJournal of Hepatology
Jahrgang70
Ausgabenummer6
Frühes Online-Datum13 Feb. 2019
PublikationsstatusVeröffentlicht - Juni 2019

Abstract

Background & Aims: Hepatitis C virus (HCV) infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors and are thus candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. Methods: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations. Chemical modeling and synthesis identified improved derivatives, while generation of susceptible and non-susceptible chimeric viruses pinpointed E1 determinants of compound sensitivity. Results: Molecules of the diphenylpiperazine, diphenylpiperidine, phenothiazine, thioxanthene, and cycloheptenepiperidine chemotypes inhibit HCV infection by interfering with membrane fusion. These molecules and a novel p-methoxy-flunarizine derivative with improved efficacy preferentially inhibit genotype 2 viral strains. Viral residues within a central hydrophobic region of E1 (residues 290–312) control susceptibility. At the same time, viral features in this region also govern pH-dependence of viral membrane fusion. Conclusions: Small molecules from different chemotypes related to flunarizine preferentially inhibit HCV genotype 2 membrane fusion. A hydrophobic region proximal to the putative fusion loop controls sensitivity to these drugs and the pH range of membrane fusion. An algorithm considering viral features in this region predicts viral sensitivity to membrane fusion inhibitors. Resistance to flunarizine correlates with more relaxed pH requirements for fusion. Lay summary: This study describes diverse compounds that act as HCV membrane fusion inhibitors. It defines viral properties that determine sensitivity to these molecules and thus provides information to identify patients that may benefit from treatment with membrane fusion inhibitors.

ASJC Scopus Sachgebiete

Ziele für nachhaltige Entwicklung

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A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors. / Banda, Dominic H.; Perin, Paula M.; Brown, Richard J.P. et al.
in: Journal of Hepatology, Jahrgang 70, Nr. 6, 06.2019, S. 1082-1092.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Banda, DH, Perin, PM, Brown, RJP, Todt, D, Solodenko, W, Hoffmeyer, P, Kumar Sahu, K, Houghton, M, Meuleman, P, Müller, R, Kirschning, A & Pietschmann, T 2019, 'A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors', Journal of Hepatology, Jg. 70, Nr. 6, S. 1082-1092. https://doi.org/10.1016/j.jhep.2019.01.033
Banda, D. H., Perin, P. M., Brown, R. J. P., Todt, D., Solodenko, W., Hoffmeyer, P., Kumar Sahu, K., Houghton, M., Meuleman, P., Müller, R., Kirschning, A., & Pietschmann, T. (2019). A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors. Journal of Hepatology, 70(6), 1082-1092. https://doi.org/10.1016/j.jhep.2019.01.033
Banda DH, Perin PM, Brown RJP, Todt D, Solodenko W, Hoffmeyer P et al. A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors. Journal of Hepatology. 2019 Jun;70(6):1082-1092. Epub 2019 Feb 13. doi: 10.1016/j.jhep.2019.01.033
Banda, Dominic H. ; Perin, Paula M. ; Brown, Richard J.P. et al. / A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors. in: Journal of Hepatology. 2019 ; Jahrgang 70, Nr. 6. S. 1082-1092.
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@article{9fe4a00e126947ba89799a8e98144822,
title = "A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors",
abstract = "Background & Aims: Hepatitis C virus (HCV) infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors and are thus candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. Methods: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations. Chemical modeling and synthesis identified improved derivatives, while generation of susceptible and non-susceptible chimeric viruses pinpointed E1 determinants of compound sensitivity. Results: Molecules of the diphenylpiperazine, diphenylpiperidine, phenothiazine, thioxanthene, and cycloheptenepiperidine chemotypes inhibit HCV infection by interfering with membrane fusion. These molecules and a novel p-methoxy-flunarizine derivative with improved efficacy preferentially inhibit genotype 2 viral strains. Viral residues within a central hydrophobic region of E1 (residues 290–312) control susceptibility. At the same time, viral features in this region also govern pH-dependence of viral membrane fusion. Conclusions: Small molecules from different chemotypes related to flunarizine preferentially inhibit HCV genotype 2 membrane fusion. A hydrophobic region proximal to the putative fusion loop controls sensitivity to these drugs and the pH range of membrane fusion. An algorithm considering viral features in this region predicts viral sensitivity to membrane fusion inhibitors. Resistance to flunarizine correlates with more relaxed pH requirements for fusion. Lay summary: This study describes diverse compounds that act as HCV membrane fusion inhibitors. It defines viral properties that determine sensitivity to these molecules and thus provides information to identify patients that may benefit from treatment with membrane fusion inhibitors.",
keywords = "Antivirals, Fusion inhibitors, Hepatitis C virus (HCV), Membrane fusion, Resistance, Humans, Drug Resistance, Viral, Structure-Activity Relationship, Flunarizine/pharmacology, Antiviral Agents/pharmacology, Hydrophobic and Hydrophilic Interactions, Hepacivirus/drug effects, Virus Internalization/drug effects, Hydrogen-Ion Concentration",
author = "Banda, {Dominic H.} and Perin, {Paula M.} and Brown, {Richard J.P.} and Daniel Todt and Wladimir Solodenko and Patrick Hoffmeyer and {Kumar Sahu}, Kamlesh and Michael Houghton and Philip Meuleman and Rolf M{\"u}ller and Andreas Kirschning and Thomas Pietschmann",
note = "Funding information: This work was funded by a grant from the Helmholtz-Alberta Initiative (HAI-IDR) to T.P. P.M.P. was funded by a scholarship of the Hannover biomedical research school within the centre for infection biology (ZIB-program). D.B. was supported by a scholarship from the Hannover School for Biomolecular Drug Research (HSBDR).",
year = "2019",
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language = "English",
volume = "70",
pages = "1082--1092",
journal = "Journal of Hepatology",
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Download

TY - JOUR

T1 - A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors

AU - Banda, Dominic H.

AU - Perin, Paula M.

AU - Brown, Richard J.P.

AU - Todt, Daniel

AU - Solodenko, Wladimir

AU - Hoffmeyer, Patrick

AU - Kumar Sahu, Kamlesh

AU - Houghton, Michael

AU - Meuleman, Philip

AU - Müller, Rolf

AU - Kirschning, Andreas

AU - Pietschmann, Thomas

N1 - Funding information: This work was funded by a grant from the Helmholtz-Alberta Initiative (HAI-IDR) to T.P. P.M.P. was funded by a scholarship of the Hannover biomedical research school within the centre for infection biology (ZIB-program). D.B. was supported by a scholarship from the Hannover School for Biomolecular Drug Research (HSBDR).

PY - 2019/6

Y1 - 2019/6

N2 - Background & Aims: Hepatitis C virus (HCV) infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors and are thus candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. Methods: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations. Chemical modeling and synthesis identified improved derivatives, while generation of susceptible and non-susceptible chimeric viruses pinpointed E1 determinants of compound sensitivity. Results: Molecules of the diphenylpiperazine, diphenylpiperidine, phenothiazine, thioxanthene, and cycloheptenepiperidine chemotypes inhibit HCV infection by interfering with membrane fusion. These molecules and a novel p-methoxy-flunarizine derivative with improved efficacy preferentially inhibit genotype 2 viral strains. Viral residues within a central hydrophobic region of E1 (residues 290–312) control susceptibility. At the same time, viral features in this region also govern pH-dependence of viral membrane fusion. Conclusions: Small molecules from different chemotypes related to flunarizine preferentially inhibit HCV genotype 2 membrane fusion. A hydrophobic region proximal to the putative fusion loop controls sensitivity to these drugs and the pH range of membrane fusion. An algorithm considering viral features in this region predicts viral sensitivity to membrane fusion inhibitors. Resistance to flunarizine correlates with more relaxed pH requirements for fusion. Lay summary: This study describes diverse compounds that act as HCV membrane fusion inhibitors. It defines viral properties that determine sensitivity to these molecules and thus provides information to identify patients that may benefit from treatment with membrane fusion inhibitors.

AB - Background & Aims: Hepatitis C virus (HCV) infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors and are thus candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets. Methods: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations. Chemical modeling and synthesis identified improved derivatives, while generation of susceptible and non-susceptible chimeric viruses pinpointed E1 determinants of compound sensitivity. Results: Molecules of the diphenylpiperazine, diphenylpiperidine, phenothiazine, thioxanthene, and cycloheptenepiperidine chemotypes inhibit HCV infection by interfering with membrane fusion. These molecules and a novel p-methoxy-flunarizine derivative with improved efficacy preferentially inhibit genotype 2 viral strains. Viral residues within a central hydrophobic region of E1 (residues 290–312) control susceptibility. At the same time, viral features in this region also govern pH-dependence of viral membrane fusion. Conclusions: Small molecules from different chemotypes related to flunarizine preferentially inhibit HCV genotype 2 membrane fusion. A hydrophobic region proximal to the putative fusion loop controls sensitivity to these drugs and the pH range of membrane fusion. An algorithm considering viral features in this region predicts viral sensitivity to membrane fusion inhibitors. Resistance to flunarizine correlates with more relaxed pH requirements for fusion. Lay summary: This study describes diverse compounds that act as HCV membrane fusion inhibitors. It defines viral properties that determine sensitivity to these molecules and thus provides information to identify patients that may benefit from treatment with membrane fusion inhibitors.

KW - Antivirals

KW - Fusion inhibitors

KW - Hepatitis C virus (HCV)

KW - Membrane fusion

KW - Resistance

KW - Humans

KW - Drug Resistance, Viral

KW - Structure-Activity Relationship

KW - Flunarizine/pharmacology

KW - Antiviral Agents/pharmacology

KW - Hydrophobic and Hydrophilic Interactions

KW - Hepacivirus/drug effects

KW - Virus Internalization/drug effects

KW - Hydrogen-Ion Concentration

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U2 - 10.1016/j.jhep.2019.01.033

DO - 10.1016/j.jhep.2019.01.033

M3 - Article

C2 - 30769006

AN - SCOPUS:85063758632

VL - 70

SP - 1082

EP - 1092

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 6

ER -

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