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PLoS Pathog. 2014 May 29;10(5):e1004166. doi: 10.1371/journal.ppat.1004166. eCollection 2014.

Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

Author information

  • 1Department of Clinical Virology, University of Gothenburg, Göteborg, Sweden.
  • 2Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland.
  • 3Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology, Göteborg, Sweden.
  • 4Institute of Virology, University of Bonn Medical Centre, Bonn, Germany.
  • 5Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands; Merck Animal Health, Bioprocess Technology & Support, Boxmeer, The Netherlands.
  • 6Department of Animal Sciences, Cell Biology and Immunology Group, Wageningen Institute of Animal Sciences, Wageningen University, Wageningen, The Netherlands.
  • 7Institute of Immunobiology, Kantonal Hospital St.Gallen, St.Gallen, Switzerland; Federal Department of Home Affairs, Institute of Virology and Immunology, Berne and Mittelhäusern, Switzerland; Vetsuisse Faculty, University of Berne, Berne, Switzerland.

Abstract

Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

PMID:
24874215
[PubMed - in process]
PMCID:
PMC4038610
Free PMC Article

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