Targeting stem-loop 1 of the SARS-CoV-2 5' UTR to suppress viral translation and Nsp1 evasion
| Autor: | Setu M. Vora, Pietro Fontana, Tianyang Mao, Valerie Leger, Ying Zhang, Tian-Min Fu, Judy Lieberman, Lee Gehrke, Ming Shi, Longfei Wang, Akiko Iwasaki, Hao Wu |
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| Rok vydání: | 2022 |
| Předmět: |
Multidisciplinary
Base Sequence SARS-CoV-2 viruses virus diseases Mice Transgenic Oligonucleotides Antisense Viral Nonstructural Proteins Virus Replication Models Biological HEK293 Cells Protein Biosynthesis Chlorocebus aethiops Host-Pathogen Interactions Animals Humans skin and connective tissue diseases 5' Untranslated Regions Vero Cells Immune Evasion |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 119(9) |
| ISSN: | 1091-6490 |
| Popis: | SARS-CoV-2 is a highly pathogenic virus that evades antiviral 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 messenger RNA (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 stem-loop 1 (SL1) region of the SARS-CoV-2 5' untranslated region (5' UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5' UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2-induced lethality in transgenic mice expressing human ACE2. 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. |
| Databáze: | OpenAIRE |
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