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Targeting Membrane-Bound Viral RNA Synthesis Reveals Potent Inhibition of Diverse Coronaviruses Including the Middle East Respiratory Syndrome Virus

Journal article
Authors Anna Lundin
R. Dijkman
Tomas Bergström
Nina Kann
Beata Adamiak
Charles Hannoun
E. Kindler
H. R. Jonsdottir
D. Muth
J. Kint
M. Forlenza
M. A. Muller
C. Drosten
V. Thiel
Edward Trybala
Published in Plos Pathogens
Volume 10
Issue 5
Pages e1004166
ISSN 1553-7366
Publication year 2014
Published at Institute of Biomedicine, Department of Infectious Medicine
Pages e1004166
Language en
Links dx.doi.org/10.1371/journal.ppat.100...
https://gup.ub.gu.se/file/133956
Keywords MOUSE HEPATITIS-VIRUS, DOUBLE-STRANDED-RNA, SARS CORONAVIRUS, REPLICATION COMPLEX, MAIN PROTEINASE, FUNCTIONAL RECEPTOR, 3C-LIKE, PROTEINASE, VACCINIA VIRUS, CELL-CULTURES, IN-VITRO, Microbiology, Parasitology, Virology
Subject categories Microbiology

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.

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