Screening of a Small Molecule Compound Library Identifies Toosendanin as an Inhibitor Against Bunyavirus and SARS-CoV-2.

Shufen Li,Meidi Ye,Yuanqiao Chen,Jiachen Li,Ke Peng,Wei Liu,Yulan Zhang,Hao Li

doi:10.3389/fphar.2021.735223

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne virus causing serious infectious disease with a high case-fatality of up to 50% in severe cases. Currently, no effective drug has been approved for the treatment of SFTSV infection. Here, we performed a high-throughput screening of a natural extracts library for compounds with activities against SFTSV infection. Three hit compounds, notoginsenoside Ft1, punicalin, and toosendanin were identified for displaying high anti-SFTSV efficacy, in which, toosendanin showed the highest inhibition potency. Mechanistic investigation indicated that toosendanin inhibited SFTSV infection at the step of virus internalization. The anti-viral effect of toosendanin against SFTSV was further verified in mouse infection models, and the treatment with toosendanin significantly reduced viral load and histopathological changes in vivo. The antiviral activity of toosendanin was further expanded to another bunyavirus and the emerging SARS-CoV-2. This study revealed a broad anti-viral effect of toosendanin and indicated its potential to be developed as an anti-viral drug for clinical use.

Highlights

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel tick-borne virus (Dabie bandavirus, formerly SFTS virus and Huaiyangshan banyangvirus), which belongs to the genus Bandavirus, family Phenuiviridae, order Bunyavirales (Yoshikawa et al, 2021)
In order to identify potent inhibitors against Severe fever with thrombocytopenia syndrome virus (SFTSV) infection, we performed a high-throughput screening (HTS) of a small molecular compound library consisting of 1,058 natural extracts (Figure 1A)
No effective drug against SFTSV infection has been approved for the treatment of SFTSV patients

Summary

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel tick-borne virus (Dabie bandavirus, formerly SFTS virus and Huaiyangshan banyangvirus), which belongs to the genus Bandavirus, family Phenuiviridae, order Bunyavirales (Yoshikawa et al, 2021). The clinical symptoms of SFTS are high fever, diarrhea, vomiting, thrombocytopenia, leukocytopenia, encephalitis, hemorrhage, and multiple organ failure with high case-fatality rate (approximately 12–50%) (Xu et al, 2011; Robles et al, 2018). SFTS was first identified in China and in South Korea, Japan, and Vietnam (Xu et al, 2011; Yu et al, 2011; Kim et al, 2013; Takahashi et al, 2014; Tran et al, 2019; Peng et al, 2020).

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