A novel viral protein translation mechanism reveals mitochondria as a target for antiviral drug development

Cheng, Zhenguo; Zhang, Danhua; Chen, Jingfei; Wu, Yifan; Liu, XiaoWen; Si, Lingling; Zhang, Zhe; Zhang, Na; Zhang, Zhongxian; Liu, Wei; Liu, Hong; Zhang, Lirong; Song, Lijie; Dunmall, Louisa S Chard; Dong, Jianzeng; Lemoine, Nicholas R; Wang, Yaohe

The ongoing Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has acutely highlighted the need to identify new treatment strategies for viral infections. Here we present a pivotal molecular mechanism of viral protein translation that relies on the mitochondrial translation machinery. We found that rare codons such as Leu-TTA are highly enriched in many viruses, including SARS-CoV-2, and these codons are essential for the regulation of viral protein expression. SARS-CoV-2 controls the translation of its spike gene by hijacking host mitochondria through 5’ leader and 3’UTR sequences that contain mitochondrial localization signals and activate the EGR1 pathway. Mitochondrial-targeted drugs such as lonidamine and polydatin significantly repress rare codon-driven gene expression and viral replication. This study identifies an unreported viral protein translation mechanism and opens up a novel avenue for developing antiviral drugs. One Sentence Summary Mitochondria are a potential target for antiviral therapy