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.; Liu, W.; Liu, H.; Zhang, L.; Song, L.; Dunmall, L. S. C.; Dong, J.; Lemoine, N. R.; Wang, Y.

doi:10.1101/2020.10.19.344713

bioRxiv · 10.1101/2020.10.19.344713

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.·Liu, W.·Liu, H.·Zhang, L.·Song, L.·Dunmall, L. S. C.·Dong, J.·Lemoine, N. R.·Wang, Y.

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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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Cheng, Z., Zhang, D., Chen, J., Wu, Y., Liu, X., Si, L., Zhang, Z., Zhang, N., Liu, W., Liu, H., Zhang, L., Song, L., Dunmall, L. S. C., Dong, J., Lemoine, N. R., Wang, Y.. 2020-10-19. A novel viral protein translation mechanism reveals mitochondria as a target for antiviral drug development. https://doi.org/10.1101/2020.10.19.344713

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