@article{eb2fa6aee2f9480db5eb27eab606c996,
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 = "Baloxavir, Heartland virus, X-ray structure, antiviral target, endonuclease, mass spectrometry, severe fever with thrombocytopenia syndrome virus",
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.}",
note = "Funding Information: We thank Ms. S. Smith for general support and coordination. Research was supported by National Institutes of Health (NIH) grants R01AI107056 and R01AI140758 (D.W.L.); R01AI123926 (G.K.A.); U19AI109945 and U19AI109664 (G.K.A.); R01GM12400701 (G.R.B.); and CA200422, AI116585, AI129496, AI140705, and AI140718 (J.U.J.); as well as by the Fletcher Jones Foundation (J.U.J.), National Science Foundation (NSF) CAREER Award MCB-1552471 (G.R.B.), and Department of Energy (DOE) Integrated Diffraction Analysis (IDAT) grant contract DE-AC02-05CH11231. The mass spectrometry was supported by the National Institute of General Medical Sciences (NIGMS) of the NIH (grant P41GM103422). Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by University of Chicago Argonne for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. The content or interpretations do not necessarily reflect the position or policies of the federal government, and no official endorsement should be inferred. W.W. W-J.S. D.W.L. J.U.J. and G.K.A. conceived the overall project. W.W. W.-J.S. Y.C. J.-S.Y. B.Z. M.I.Z. T.E.F. D.W.L. and G.K.A. performed the research. D.W.L. M.L.G. G.R.B. J.U.J. and G.K.A. supervised the research. W.W. and W.-J.S. wrote the initial manuscript draft with significant assistance from J.U.J. D.W.L. and G.K.A. All authors participated in the data analysis and assisted in the manuscript preparation. The authors declare no competing interests. Funding Information: We thank Ms. S. Smith for general support and coordination. Research was supported by National Institutes of Health ( NIH ) grants R01AI107056 and R01AI140758 (D.W.L.); R01AI123926 (G.K.A.); U19AI109945 and U19AI109664 (G.K.A.); R01GM12400701 (G.R.B.); and CA200422 , AI116585 , AI129496 , AI140705 , and AI140718 (J.U.J.); as well as by the Fletcher Jones Foundation (J.U.J.), National Science Foundation ( NSF ) CAREER Award MCB-1552471 (G.R.B.), and Department of Energy ( DOE ) Integrated Diffraction Analysis (IDAT) grant contract DE-AC02-05CH11231 . The mass spectrometry was supported by the National Institute of General Medical Sciences ( NIGMS ) of the NIH (grant P41GM103422 ). Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by University of Chicago Argonne for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. The content or interpretations do not necessarily reflect the position or policies of the federal government, and no official endorsement should be inferred. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2020",
month = jan,
day = "7",
doi = "10.1016/j.celrep.2019.12.020",
language = "English",
volume = "30",
pages = "153--163.e5",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}