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Chlorcyclizine Inhibits Viral Fusion of Hepatitis C Virus Entry by Directly Targeting HCV Envelope Glycoprotein 1.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2020 Jul 16; Vol. 27 (7), pp. 780-792.e5. Date of Electronic Publication: 2020 May 07. - Publication Year :
- 2020
-
Abstract
- Chlorcyclizine (CCZ) is a potent hepatitis C virus (HCV) entry inhibitor, but its molecular mechanism is unknown. Here, we show that CCZ directly targets the fusion peptide of HCV E1 and interferes with the fusion process. Generation of CCZ resistance-associated substitutions of HCV in vitro revealed six missense mutations in the HCV E1 protein, five being in the putative fusion peptide. A viral fusion assay demonstrated that CCZ blocked HCV entry at the membrane fusion step and that the mutant viruses acquired resistance to CCZ's action in blocking membrane fusion. UV cross-linking of photoactivatable CCZ-diazirine-biotin in both HCV-infected cells and recombinant HCV E1/E2 protein demonstrated direct binding to HCV E1 glycoprotein. Mass spectrometry analysis revealed that CCZ cross-linked to an E1 sequence adjacent to the putative fusion peptide. Docking simulations demonstrate a putative binding model, wherein CCZ binds to a hydrophobic pocket of HCV E1 and forms extensive interactions with the fusion peptide.<br />Competing Interests: Declaration of Interests The authors declare no competing interests.<br /> (Published by Elsevier Ltd.)
- Subjects :
- Antiviral Agents chemical synthesis
Antiviral Agents chemistry
Antiviral Agents pharmacology
Binding Sites
Biotin chemistry
Diazomethane chemistry
Drug Resistance, Viral drug effects
Genotype
Hepacivirus drug effects
Hepacivirus genetics
Humans
Membrane Fusion drug effects
Molecular Docking Simulation
Piperazines metabolism
Piperazines pharmacology
Ultraviolet Rays
Viral Envelope Proteins metabolism
Virus Internalization drug effects
Hepacivirus metabolism
Piperazines chemistry
Viral Envelope Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 27
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 32386595
- Full Text :
- https://doi.org/10.1016/j.chembiol.2020.04.006