Anisomycin inhibits Coxsackievirus B replication by promoting the lysosomal degradation of eEF1A1.

Enze Shao, Shuoxuan Zhao, Yanyan Dong, Yao Wang, Yanru Fei, Siwei Li, Lixin Wang, Tahira Bashir, Tian Luan, Lexun Lin, Yan Wang, Wenran Zhao, Zhaohua Zhong

Antiviral research 2023 Jul

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Group B Coxsackieviruses (CVB) are non-enveloped small RNA viruses in the genus Enterovirus, family Picornaviridae. CVB infection causes diverse conditions from common cold to myocarditis, encephalitis, and pancreatitis. No specific antiviral is available for the treatment of CVB infection. Anisomycin, a pyrrolidine-containing antibiotic and translation inhibitor, was reported to inhibit the replication of some picornaviruses. However, it is unknown if anisomycin can act as an antiviral against CVB infection. Here we observed that anisomycin showed potent inhibition on CVB type 3 (CVB3) infection with negligible cytotoxicity when applied at the early stage of virus infection. Mice infected with CVB3 showed markedly alleviated myocarditis with reduced viral replication. We found that CVB3 infection significantly increased the transcription of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). CVB3 replication was suppressed by EEF1A1 knockdown, while elevated by EEF1A1 overexpression. Similar to the effect of CVB3 infection, EEF1A1 transcription was increased in response to anisomycin treatment. However, eEF1A1 protein level was decreased with anisomycin treatment in a dose-dependent manner in CVB3-infected cells. Moreover, anisomycin promoted eEF1A1 degradation, which was inhibited by the treatment of chloroquine but not MG132. We demonstrated that eEF1A1 interacted with the heat shock cognate protein 70 (HSP70), and eEF1A1 degradation was inhibited by LAMP2A knockdown, implicating that eEF1A1 is degraded through chaperone-mediated autophagy. Taken together, we demonstrated that anisomycin, which inhibits CVB replication through promoting the lysosomal degradation of eEF1A1, could be a potential antiviral candidate for the treatment of CVB infection. Copyright © 2023 Elsevier B.V. All rights reserved.

Citation

Enze Shao, Shuoxuan Zhao, Yanyan Dong, Yao Wang, Yanru Fei, Siwei Li, Lixin Wang, Tahira Bashir, Tian Luan, Lexun Lin, Yan Wang, Wenran Zhao, Zhaohua Zhong. Anisomycin inhibits Coxsackievirus B replication by promoting the lysosomal degradation of eEF1A1. Antiviral research. 2023 Jul;215:105621