Antiviral activity of the HSP90 inhibitor VER-50589 against enterovirus 71.

Abstract

Enterovirus 71 (EV71) is the major pathogen responsible for hand, foot, and mouth disease (HFMD) outbreaks; to date, there is no specific anti-EV71 agent. HSP90 is a crucial host factor for the viral life cycle and an ideal therapeutic target for limiting viral proliferation. However, the specific role of HSP90 in EV71-related signaling pathways and anti-EV71 agents targeting HSP90 remains unclear. This study aimed to verify the role of HSP90 in signaling pathways involved in EV71 replication and investigate the antiviral effects of a small molecule of VER-50589, a potent HSP90 inhibitor, against EV71 both in vitro and in vivo. Viral plaque assay, western blotting, and qPCR results showed that VER-50589 diminished the plaque formation induced by EV71 and inhibited EV71 mRNA and protein synthesis. A single daily dose of VER-50589 treatment significantly improved the survival rate of EV71-infected mice (p < 0.005). Interestingly, VER-50589 also exhibits activities against a series of human enteroviruses, including Coxsackievirus B3 (CVB3), Coxsackievirus B4-5 (CVB4-5), Coxsackievirus B4-7 (CVB4-7), and Echovirus 11 (Echo11). EV71 infection activated the AKT and ERK signaling pathways, and phosphorylation of AKT and RAF/MEK/ERK was weakened by VER-50589 administration. Thus, VER-50589 exhibits robust antiviral activity by inhibiting HSP90 and mediating the AKT and RAF/MEK/ERK signaling pathways. Considering that there are no effective antivirals or vaccines for the prevention and cure of HFMD in a clinical setting, the development of an anti-EV71 agent would be a straightforward and feasible therapeutic approach.

• Authors: Guangyan Zhu, Chengyuan Wu, Qian Wang, Danchun Deng, Binbin Lin, Xujuan Hu, Fang Qiu, Zhengnan Li, Chaolin Huang, Qingyu Yang, Dingyu Zhang
• Journal: Antiviral research (Antiviral Res) Vol. 211 Pg. 105553 (03 2023) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 36737007 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• VER-50589
• Proto-Oncogene Proteins c-akt
• Antiviral Agents
• Antineoplastic Agents
• Mitogen-Activated Protein Kinase Kinases

Topics

• Mice
• Humans
• Animals
• Enterovirus A, Human
• Proto-Oncogene Proteins c-akt (metabolism)
• Antiviral Agents (pharmacology)
• Virus Replication
• Enterovirus
• Enterovirus Infections (drug therapy)
• Antineoplastic Agents (pharmacology)
• Mitogen-Activated Protein Kinase Kinases