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

authored by

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

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.

Organisation(s)

Institute of Organic Chemistry
Centre of Biomolecular Drug Research (BMWZ)

External Organisation(s)

Ruhr-Universität Bochum
University of Alberta
Ghent University
TWINCORE Zentrum für Experimentelle und Klinische Infektionsforschung GmbH
German Center for Infection Research (DZIF)
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)

Type

Article

Journal

Journal of Hepatology

Volume

70

Pages

1082-1092

No. of pages

11

ISSN

0168-8278

Publication date

06.2019

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Hepatology

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

http://hdl.handle.net/1854/LU-8584919 (Access: Open)
https://doi.org/10.1016/j.jhep.2019.01.033 (Access: Closed)