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
Affiliations
Wenjie Wang
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
Woo-Jin Shin
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Bojie Zhang
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA
Younho Choi
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Ji-Seung Yoo
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Maxwell I. Zimmerman
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
Thomas E. Frederick
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
Gregory R. Bowman
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA
Michael L. Gross
Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, USA
Daisy W. Leung
Division of Infectious Diseases, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
Jae U. Jung
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Corresponding author
Gaya K. Amarasinghe
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Corresponding author
Summary: 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. : Wang et al. solve the X-ray crystal structure of SFTSV L endonuclease domain and investigate the characteristics of SFTSV and HRTV endonuclease function. Resulting data support a mechanism for regulation. Baloxavir effectively inhibits the endonuclease activity of SFTSV and HRTV. Keywords: severe fever with thrombocytopenia syndrome virus, Heartland virus, endonuclease, X-ray structure, antiviral target, mass spectrometry, Baloxavir