Micrococcin P1, a naturally occurring macrocyclic peptide inhibiting hepatitis C virus entry in a pan-genotypic manner

Antiviral Res. 2016 Aug:132:287-95. doi: 10.1016/j.antiviral.2016.07.002. Epub 2016 Jul 4.

Abstract

Hepatitis C virus (HCV) is considered a major public health concern worldwide. Despite recent advances in curing chronic hepatitis C, unmet medical needs still remain, especially due to the high economic burden of therapies. Accordingly, our study aimed to identify affordable novel HCV inhibitors by screening of natural product compound libraries. We identified micrococcin P1, a macrocyclic peptide antibiotic, inhibiting HCV entry in a pan-genotypic manner with an EC50 range of 0.1-0.5 μM. Micrococcin P1 interfered with HCV entry at an attachment step. Furthermore, micrococcin P1 efficiently inhibited HCV spread by blocking cell-free infection as well as cell-to-cell transmission, without affecting the secretion of infectious virions. Interestingly, the putative molecular target of micrococcin P1 is glycoprotein E2 (IIe-630-Thr), as revealed by selection for viral drug resistance. In addition, micrococcin P1 inhibited sofosbuvir-resistant HCV strains and showed synergy in combination with selected HCV drugs, suggesting an alternative treatment paradigm for patients. In conclusion, we identified micrococcin P1 as specifically inhibiting entry of all HCV genotypes and demonstrated that micrococcin P1 potentially could add value to therapies in combination with current HCV interventions.

Keywords: Antiviral inhibitor; HCV entry; Hepatitis C virus; Micrococcin P1; Pan-genotypic inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Bacteriocins / chemistry
  • Bacteriocins / pharmacology*
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Resistance, Viral / drug effects
  • Drug Synergism
  • Genotype*
  • Hepacivirus / drug effects*
  • Hepacivirus / physiology*
  • Hepatitis C / drug therapy
  • Hepatitis C / virology
  • Humans
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Virus Internalization / drug effects*
  • Virus Release / drug effects
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Bacteriocins
  • Peptides
  • micrococcin