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Targeting stem-loop 1 of the SARS-CoV-2 5' UTR to suppress viral translation and Nsp1 evasion.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Mar 01; Vol. 119 (9). - Publication Year :
- 2022
-
Abstract
- 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.<br />Competing Interests: The authors declare no competing interest.<br /> (Copyright © 2022 the Author(s). Published by PNAS.)
- Subjects :
- Animals
Base Sequence
Chlorocebus aethiops
HEK293 Cells
Host-Pathogen Interactions drug effects
Host-Pathogen Interactions genetics
Humans
Immune Evasion drug effects
Mice, Transgenic
Models, Biological
Oligonucleotides, Antisense pharmacology
SARS-CoV-2 drug effects
Vero Cells
Virus Replication drug effects
5' Untranslated Regions genetics
Immune Evasion genetics
Protein Biosynthesis drug effects
SARS-CoV-2 genetics
Viral Nonstructural Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 119
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 35149555
- Full Text :
- https://doi.org/10.1073/pnas.2117198119