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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

1
State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
2
Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
3
Carol Yu Centre for Infection, Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
4
Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou 571101, China, and The University of Hong Kong, Pokfulam, Hong Kong, China
5
Department of Pathogen Biology, Hainan Medical University, Haikou 571101, China
6
Key Laboratory of Translational Tropical Medicine, Hainan Medical University, Haikou 571101, China
7
Key Laboratory for Medical Virology and National Institute for Viral Disease Control and Prevention, Chinese Centre for Disease Control and Prevention, Beijing 102206, China
8
School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong, China
9
The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Pokfulam, Hong Kong, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Viruses 2019, 11(4), 385; https://doi.org/10.3390/v11040385
Received: 16 April 2019 / Revised: 23 April 2019 / Accepted: 24 April 2019 / Published: 25 April 2019
(This article belongs to the Special Issue Viral Entry Pathways)
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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. View Full-Text
Keywords: antiviral; broxyquinoline; bunyavirales; eltrombopag; entry; hexachlorophene; Huaiyangshan banyangvirus; regorafenib; SFTSV; triclosan antiviral; broxyquinoline; bunyavirales; eltrombopag; entry; hexachlorophene; Huaiyangshan banyangvirus; regorafenib; SFTSV; triclosan
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Yuan, S.; Chan, J.F.; Ye, Z.-W.; Wen, L.; Tsang, T.G.; Cao, J.; Huang, J.; Chan, C.C.; Chik, K.K.; Choi, G.K.; Cai, J.-P.; Yin, F.; Chu, H.; Liang, M.; Jin, D.-Y.; Yuen, K.-Y. Screening of an FDA-Approved Drug Library with a Two-Tier System Identifies an Entry Inhibitor of Severe Fever with Thrombocytopenia Syndrome Virus. Viruses 2019, 11, 385.

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