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Screening of an FDA-Approved Drug Library with a Two-Tier System Identifies an Entry Inhibitor of Severe Fever with Thrombocytopenia Syndrome Virus

Authors :
Shuofeng Yuan
Jasper Fuk-Woo Chan
Zi-Wei Ye
Lei Wen
Terance Gi-Wai Tsang
Jianli Cao
Jingjing Huang
Chris Chun-Yiu Chan
Kenn Ka-Heng Chik
Garnet Kwan-Yue Choi
Jian-Piao Cai
Feifei Yin
Hin Chu
Mifang Liang
Dong-Yan Jin
Kwok-Yung Yuen
Source :
Viruses, Vol 11, Iss 4, p 385 (2019)
Publication Year :
2019
Publisher :
MDPI AG, 2019.

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case-fatality rates of up to 30%. There are currently very limited treatment options for SFTSV infection. We conducted a drug repurposing program by establishing a two-tier test system to rapidly screen a Food and Drug Administration- (FDA)-approved drug library for drug compounds with anti-SFTSV activity in vitro. We identified five drug compounds that inhibited SFTSV replication at low micromolar concentrations, including hexachlorophene, triclosan, regorafenib, eltrombopag, and broxyquinoline. Among them, hexachlorophene was the most potent with an IC50 of 1.3 ± 0.3 µM and a selectivity index of 18.7. Mechanistic studies suggested that hexachlorophene was a virus entry inhibitor, which impaired SFTSV entry into host cells by interfering with cell membrane fusion. Molecular docking analysis predicted that the binding of hexachlorophene with the hydrophobic pocket between domain I and domain III of the SFTSV Gc glycoprotein was highly stable. The novel antiviral activity and mechanism of hexachlorophene in this study would facilitate the use of hexachlorophene as a lead compound to develop more entry inhibitors with higher anti-SFTSV potency and lower toxicity.

Details

Language :
English
ISSN :
19994915
Volume :
11
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Viruses
Publication Type :
Academic Journal
Accession number :
edsdoj.2caedffb9a9141ce900fb4760723a349
Document Type :
article
Full Text :
https://doi.org/10.3390/v11040385