A novel viral protein translation mechanism reveals mitochondria as a target for antiviral drug development
Cheng, Z.; Zhang, D.; Chen, J.; Wu, Y.; Liu, X.; Si, L.; Zhang, Z.; Zhang, N.; Zhang, Z.; Liu, W.; Liu, H.; Zhang, L.; Song, L.; Dunmall, L. S. C.; Dong, J.; Lemoine, N. R.; Wang, Y.
Show abstract
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 3UTR 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 SummaryMitochondria are a potential target for antiviral therapy
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