Identification of a novel binding inhibitor that blocks the interaction between hSCARB2 and VP1 of enterovirus 71

Qi Tang; Zhichao Xu; Fan Zhang; Yang Cai; Yinuo Chen; Baojing Lu; Hai-Bing Zhou; Ke Lan; Shuwen Wu

doi:10.1016/j.cellin.2022.100016

Identification of a novel binding inhibitor that blocks the interaction between hSCARB2 and VP1 of enterovirus 71

Cell Insight. 2022 Feb 12;1(2):100016. doi: 10.1016/j.cellin.2022.100016. eCollection 2022 Apr.

Authors

Qi Tang^{1

2}, Zhichao Xu³, Fan Zhang², Yang Cai², Yinuo Chen², Baojing Lu¹, Hai-Bing Zhou^{3

4}, Ke Lan^{2

5}, Shuwen Wu²

Affiliations

¹ Department of Microbiology, The Key Laboratory of Microbiology and Parasitology of Anhui Province, The Key Laboratory of Zoonoses of High Institutions in Anhui, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
² State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430071, China.
³ Hubei Provincial Key Laboratory of Developmentally Originated Disease, Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
⁴ Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
⁵ Medical Research Institute, Wuhan University, Wuhan, 430071, China.

Abstract

Enterovirus 71 (EV-A71) infection causes severe hand-foot-and-mouth disease that leads to cardiopulmonary complications and death in young children under 5 years of age. Although there are available vaccines for EV-A71 C⁴, however, there are no efficient drugs for severe cases. Thus, there is an urgent need to find new direct-antiviral agents (DAAs) to control EV-A71 infection. In this study, we report our discovery of the EV-A71 capsid inhibitor PTC-209HBr, a small-molecule Bmi-1 inhibitor and an anticancer agent, and its derivatives that inhibit multiple enteroviruses with an EC₅₀ at a submicromolar efficacy. The mechanism of action of PTC-209HBr was confirmed by time-of-addition, resistance selection and reverse genetics experiments, microscale thermophoresis (MST), viral binding and entry assays, coimmunoprecipitation (Co-IP) and immunofluorescence experiments (IF). Mechanistic studies indicated that PTC-209HBr inhibited EV-A71 infection by impeding the binding between VP1 and the receptor hSCARB2 during the early stage of EV-A71 infection through hindering viral entry into host cells. Collectively, these findings indicated that PCT-209HBr is a novel inhibitor of enteroviruses with a confirmed mechanism of action that can be further developed into EV-A71 DAAs.

Keywords: DAAs; EV-A71; Enterovirus; Enviroxime; PTC-209HBr; Pirodavir; VP1; hSCARB2.