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

Dong-Yan Jin,Mifang Liang,Jianli Cao,Feifei Yin,Garnet Kwan-Yue Choi,Kwok-Yung Yuen,Jasper Fuk-Woo Chan,Terance Gi-Wai Tsang,Kenn Ka-Heng Chik,Jingjing Huang,Hin Chu,Shuofeng Yuan,Lei Wen,Chris Chun-Yiu Chan,Jian-Piao Cai,Zi-Wei Ye

doi:10.3390/v11040385

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.

Highlights

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus in the genus Banyangvirus, family Phenuiviridae, order Bunyavirales
We first established a robust two-tier (ELISA followed by viral load reduction assay) screening platform for SFTSV. Using this drug screening platform, we identified five drug compounds with anti-SFTSV activity in vitro, and characterized the anti-SFTSV mechanism of the most potent drug, hexachlorophene, as an entry inhibitor of SFTSV
AsAs exemplified by the recent epidemics caused by severe acute respiratory syndrome and Middle exemplified by the recent epidemics caused by severe acute respiratory syndrome and East respiratory

Summary

Introduction

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus in the genus Banyangvirus, family Phenuiviridae, order Bunyavirales. It was first identified in Huaiyangshan, a mountainous area in Huaiyang County in the Henan province of China [1]. The virus has been isolated from infected humans, ticks, and mammals in Japan and South Korea. SFTSV is so named as it causes severe fever with thrombocytopenia syndrome (SFTS), an acute febrile illness characterized by high fever, thrombocytopenia, and hemorrhagic complications in infected humans. The mortality rate of SFTS may be as high as 17% to 30% [1,2]

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