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bioRxiv · 10.1101/2021.09.09.459641

Targeting Stem-loop 1 of the SARS-CoV-2 5'UTR to suppress viral translation and Nsp1 evasion

Vora, S. M.·Fontana, P.·Leger, V.·Zhang, Y.·Fu, T.-M.·Lieberman, J.·Gehrke, L.·Shi, M.·Wang, L.·Wu, H.
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Abstract

SARS-CoV-2 is a highly pathogenic virus that evades anti-viral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the mRNA entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the SL1 region of the SARS-CoV-2 5 UTR is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides (ASOs) inhibits viral translation and makes SARS-CoV-2 5 UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus own virulence mechanism against itself could force a critical trade off between drug resistance and pathogenicity.

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Vora, S. M., Fontana, P., Leger, V., Zhang, Y., Fu, T.-M., Lieberman, J., Gehrke, L., Shi, M., Wang, L., Wu, H.. 2021-09-09. Targeting Stem-loop 1 of the SARS-CoV-2 5'UTR to suppress viral translation and Nsp1 evasion. https://doi.org/10.1101/2021.09.09.459641

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