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Sci Transl Med. 2017 Jun 28;9(396). pii: eaal3653. doi: 10.1126/scitranslmed.aal3653.

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses.

Author information

1
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
3
Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.
4
Gilead Sciences Inc., Foster City, CA 94404, USA.
5
Division of Infectious Diseases, Department of Pediatrics and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. mark.denison@vanderbilt.edu rbaric@email.unc.edu.
6
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. mark.denison@vanderbilt.edu rbaric@email.unc.edu.

Abstract

Emerging viral infections are difficult to control because heterogeneous members periodically cycle in and out of humans and zoonotic hosts, complicating the development of specific antiviral therapies and vaccines. Coronaviruses (CoVs) have a proclivity to spread rapidly into new host species causing severe disease. Severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) successively emerged, causing severe epidemic respiratory disease in immunologically naïve human populations throughout the globe. Broad-spectrum therapies capable of inhibiting CoV infections would address an immediate unmet medical need and could be invaluable in the treatment of emerging and endemic CoV infections. We show that a nucleotide prodrug, GS-5734, currently in clinical development for treatment of Ebola virus disease, can inhibit SARS-CoV and MERS-CoV replication in multiple in vitro systems, including primary human airway epithelial cell cultures with submicromolar IC50 values. GS-5734 was also effective against bat CoVs, prepandemic bat CoVs, and circulating contemporary human CoV in primary human lung cells, thus demonstrating broad-spectrum anti-CoV activity. In a mouse model of SARS-CoV pathogenesis, prophylactic and early therapeutic administration of GS-5734 significantly reduced lung viral load and improved clinical signs of disease as well as respiratory function. These data provide substantive evidence that GS-5734 may prove effective against endemic MERS-CoV in the Middle East, circulating human CoV, and, possibly most importantly, emerging CoV of the future.

PMID:
28659436
PMCID:
PMC5567817
DOI:
10.1126/scitranslmed.aal3653
[Indexed for MEDLINE]
Free PMC Article

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