The Cap-Snatching SFTSV Endonuclease Domain Is an Antiviral Target

被引：29

作者：

Wang, Wenjie ^{[1
]}

Shin, Woo-Jin ^{[2
]}

Zhang, Bojie ^{[3
]}

Choi, Younho ^{[2
]}

Yoo, Ji-Seung ^{[2
]}

Zimmerman, Maxwell I. ^{[4
]}

Frederick, Thomas E. ^{[4
]}

Bowman, Gregory R. ^{[4
]}

Gross, Michael L. ^{[3
]}

Leung, Daisy W. ^{[5
]}

Jung, Jae U. ^{[2
]}

Amarasinghe, Gaya K. ^{[1
]}

机构：

[1] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[2] Univ Southern Calif, Keck Sch Med, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA

[3] Washington Univ, Dept Chem, St Louis, MO 63130 USA

[4] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, John T Milliken Dept Med, Div Infect Dis, St Louis, MO 63110 USA

来源：

CELL REPORTS | 2020年 / 30卷 / 01期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

SEVERE FEVER; THROMBOCYTOPENIA SYNDROME; STRUCTURE REFINEMENT; HUAIYANGSHAN VIRUS; RIBAVIRIN THERAPY; POLYMERASE; BUNYAVIRUS; INFECTION; PA; PATHOGENESIS;

D O I：

10.1016/j.celrep.2019.12.020

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-angstrom 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 similar to 100 nM in enzyme inhibition and an EC50 value of similar to 250 nM against SFTSV and HRTV in plaque assays. Together, our data support sNSV endonucleases as an antiviral target.

引用

页码：153 / +

页数：16