The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

Wang, Wenjie; Shin, Woo-Jin; Zhang, Bojie; Choi, Younho; Yoo, Ji-Seung; Zimmerman, Maxwell I.; Frederick, Thomas E.; Bowman, Gregory R.; Gross, Michael L.; Leung, Daisy W.; Jung, Jae U.; Amarasinghe, Gaya K.

doi:10.1016/j.celrep.2019.12.020

Title: The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

Journal Article · 07 January 2020 · Cell Reports

DOI: https://doi.org/10.1016/j.celrep.2019.12.020 · OSTI ID:1581467

Wang, Wenjie ^[1]; Shin, Woo-Jin ^[2]; Zhang, Bojie ^[3]; Choi, Younho ^[2]; Yoo, Ji-Seung ^[2]; Zimmerman, Maxwell I. ^[1]; Frederick, Thomas E. ^[1]; Bowman, Gregory R. ^[1]; Gross, Michael L. ^[3]; Leung, Daisy W. ^[1]; Jung, Jae U. ^[2]; Amarasinghe, Gaya K. ^[1]

Washington Univ., St. Louis, MO (United States). School of Medicine
Univ. of Southern California, Los Angeles, CA (United States). Keck School of Medicine
Washington Univ., St. Louis, MO (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 1581467

Alternate ID(s):: OSTI ID: 1598032

Journal Information:: Cell Reports, Vol. 30, Issue 1; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 24 works

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59 BASIC BIOLOGICAL SCIENCES
severe fever with thrombocytopenia syndrome virus
Heartland virus
endonuclease
X-ray structure
antiviral target
mass spectrometry
Baloxavir

Title: The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

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