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Cell Rep. 2020 Jan 7;30(1):153-163.e5. doi: 10.1016/j.celrep.2019.12.020.

The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
3
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA.
4
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Division of Infectious Diseases, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: jaeujung@med.usc.edu.
7
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: gamarasinghe@wustl.edu.

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%-30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While the overall structure is similar to those of other cap-snatching sNSV endonucleases, differences near the C terminus of the SFTSV endonuclease suggest divergence in regulation. Influenza virus endonuclease inhibitors, including the US Food and Drug Administration (FDA) approved Baloxavir (BXA), inhibit the endonuclease activity in in vitro enzymatic assays and in cell-based studies. BXA displays potent activity with a half maximal inhibitory concentration (IC50) of ∼100 nM in enzyme inhibition and an EC50 value of ∼250 nM against SFTSV and HRTV in plaque assays. Together, our data support sNSV endonucleases as an antiviral target.

KEYWORDS:

Baloxavir; Heartland virus; X-ray structure; antiviral target; endonuclease; mass spectrometry; severe fever with thrombocytopenia syndrome virus

PMID:
31914382
DOI:
10.1016/j.celrep.2019.12.020
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