Details
| Original language | English |
|---|---|
| Pages (from-to) | 1082-1092 |
| Number of pages | 11 |
| Journal | Journal of Hepatology |
| Volume | 70 |
| Issue number | 6 |
| Early online date | 13 Feb 2019 |
| Publication status | Published - Jun 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.
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
ASJC Scopus subject areas
- Medicine(all)
- Hepatology
Sustainable Development Goals
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In: Journal of Hepatology, Vol. 70, No. 6, 06.2019, p. 1082-1092.
Research output: Contribution to journal › Article › Research › peer review
}
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
UR - http://www.scopus.com/inward/record.url?scp=85063758632&partnerID=8YFLogxK
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 -