The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

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

doi:10.1016/j.celrep.2019.12.020

The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

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

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26 Scopus citations

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.

Original language	English
Pages (from-to)	153-163.e5
Journal	Cell Reports
Volume	30
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2019.12.020
State	Published - 7 Jan 2020

Keywords

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

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10.1016/j.celrep.2019.12.020

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title = "The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target",

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-{\AA} 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 = "antiviral target, Baloxavir, endonuclease, Heartland virus, mass spectrometry, severe fever with thrombocytopenia syndrome virus, X-ray structure",

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

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AU - Shin, Woo Jin

AU - Zhang, Bojie

AU - Choi, Younho

AU - Yoo, Ji Seung

AU - Zimmerman, Maxwell I.

AU - Frederick, Thomas E.

AU - Bowman, Gregory R.

AU - Gross, Michael L.

AU - Leung, Daisy W.

AU - Jung, Jae U.

AU - Amarasinghe, Gaya K.

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KW - endonuclease

KW - Heartland virus

KW - mass spectrometry

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The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

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