Structure-based virtual screening of ROCK1 inhibitors for the discovery of Enterovirus-A71 antivirals

Rui Qiao; Wanggang Tang; Jiayan Li; Chen Li; Chaoyue Zhao; Xun Wang; Minghui Li; Yuchen Cui; Yanjia Chen; Guonan Cai; Qingyu Wu; Xiaoyu Zhao; Pengfei Wang

doi:10.1016/j.virol.2023.06.011

Structure-based virtual screening of ROCK1 inhibitors for the discovery of Enterovirus-A71 antivirals

Virology. 2023 Aug:585:205-214. doi: 10.1016/j.virol.2023.06.011. Epub 2023 Jun 21.

Authors

Rui Qiao¹, Wanggang Tang², Jiayan Li¹, Chen Li¹, Chaoyue Zhao¹, Xun Wang¹, Minghui Li¹, Yuchen Cui¹, Yanjia Chen¹, Guonan Cai¹, Qingyu Wu¹, Xiaoyu Zhao³, Pengfei Wang⁴

Affiliations

¹ Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Institute of Infectious Disease and Biosecurity, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China.
² Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, Bengbu Medical College, Bengbu, Anhui, China.
³ Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Institute of Infectious Disease and Biosecurity, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China. Electronic address: xiaoyu_zhao@fudan.edu.cn.
⁴ Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai Institute of Infectious Disease and Biosecurity, State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, School of Life Sciences, Fudan University, Shanghai, China. Electronic address: pengfei_wang@fudan.edu.cn.

PMID: 37384967
DOI: 10.1016/j.virol.2023.06.011

Abstract

Human enterovirus A71 (EV-A71) is the major causative agent of hand, foot, and mouth disease (HFMD), which may lead to neurological sequelae and even death. Although EV-A71 seriously threatens public health, there remains no efficient drug for the treatment of EV-A71 infection. We previously demonstrated that ROCK1 is a novel host dependency factor for EV-A71 replication and can serve as a target for the development of anti-EV-A71 therapeutics. In this study, we identified a subset of inhibitors with potential anti-EV-A71 activity by virtual screening using ROCK1 as a target. Among the hits, Dasabuvir, an HCV polymerase inhibitor, was found to have the best antiviral activity which is consistent with the ranking scores in Autodock Vina and iGEMDOCK. We found that Dasabuvir efficiently suppressed EV-A71 replication in a dose-dependent manner. Moreover, Dasabuvir not only efficiently suppressed the replication of EV-A71 in RD cells, but also in multiple cell lines, including HEK-293T, Caco-2, HT-29, HepG2, and Huh7. Besides, Dasabuvir alleviated the release of proinflammatory cytokines caused by EV-A71 infection. Notably, Dasabuvir also exhibited antiviral activity of CVA10, indicating it may have broad-spectrum antiviral activity against species Enteroviruses A. Hence, our results further confirm that ROCK1 can be a potential drug target and suggest Dasabuvir could be a clinical candidate for the treatment of EV-A71 infection.

Keywords: Antiviral agent; EV-A71; ROCK1; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology
Caco-2 Cells
Enterovirus A, Human*
Enterovirus Infections* / drug therapy
Enterovirus*
Hand, Foot and Mouth Disease*
Humans
rho-Associated Kinases

Substances

dasabuvir
Antiviral Agents
ROCK1 protein, human
rho-Associated Kinases