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

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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.

Authors:: 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.

Publication Date:: Wed Jan 01 00:00:00 EST 2020

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

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

OSTI Identifier:: 1581467

Alternate Identifier(s):: OSTI ID: 1598032

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

Resource Type:: Published Article

Journal Name:: Cell Reports

Additional Journal Information:: Journal Name: Cell Reports Journal Volume: 30 Journal Issue: 1; Journal ID: ISSN 2211-1247

Publisher:: Elsevier

Country of Publication:: Netherlands

Language:: English

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

Citation Formats


                    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., and Amarasinghe, Gaya K. The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target.  Netherlands: N. p., 2020. 
Web.  doi:10.1016/j.celrep.2019.12.020.

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                    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. The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target.  Netherlands.  https://doi.org/10.1016/j.celrep.2019.12.020

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                    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., and Amarasinghe, Gaya K. Wed .  
"The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target".  Netherlands.  https://doi.org/10.1016/j.celrep.2019.12.020.

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@article{osti_1581467,

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

  author       = {Wang, Wenjie and Shin, Woo-Jin and Zhang, Bojie and Choi, Younho 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.},

  abstractNote = {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.},

  doi          = {10.1016/j.celrep.2019.12.020},

  journal      = {Cell Reports},

  number       = 1,

  volume       = 30,

  place        = {Netherlands},

  year         = {Wed Jan 01 00:00:00 EST 2020},

  month        = {Wed Jan 01 00:00:00 EST 2020}

}

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