Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus
Artikel i vetenskaplig tidskrift, 2014

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.

SARS CORONAVIRUS

IN-VITRO

DOUBLE-STRANDED-RNA

3C-LIKE

CELL-CULTURES

Microbiology

PROTEINASE

REPLICATION COMPLEX

VACCINIA VIRUS

Parasitology

MAIN PROTEINASE

FUNCTIONAL RECEPTOR

Virology

MOUSE HEPATITIS-VIRUS

Författare

Anna Lundin

Göteborgs universitet

R. Dijkman

Federal Department of Home Affairs

Kantonsspital St Gallen

Tomas Bergström

Göteborgs universitet

Nina Kann

Chalmers, Kemi- och bioteknik, Organisk kemi

Beata Adamiak

Göteborgs universitet

Charles Hannoun

Göteborgs universitet

E. Kindler

Kantonsspital St Gallen

Federal Department of Home Affairs

H. R. Jonsdottir

Federal Department of Home Affairs

Kantonsspital St Gallen

D. Muth

Universität Bonn

J. Kint

Wageningen University and Research Centre

Merck Animal Health

M. Forlenza

Wageningen University and Research Centre

M. A. Muller

Universität Bonn

C. Drosten

Universität Bonn

V. Thiel

Universität Bern

Federal Department of Home Affairs

Kantonsspital St Gallen

Edward Trybala

Göteborgs universitet

PLoS Pathogens

1553-7366 (ISSN) 1553-7374 (eISSN)

Vol. 10 5 e1004166- e1004166

Ämneskategorier

Mikrobiologi

DOI

10.1371/journal.ppat.1004166

Mer information

Senast uppdaterat

2018-04-03