ArticleProceedings of the National Academy of Sciences of the United States of America2022
Targeting stem-loop 1 of the SARS-CoV-2 5' UTR to suppress viral translation and Nsp1 evasion.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers.
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80 citing papers in PubMed, 111 citations in OpenAlex.
- Bridging the antiviral gap: A BAC-based non-infectious SARS-CoV-2 replicon reveals potent antisense gapmers.Molecular therapy. Nucleic acids · 2026Article
- Raman Analysis of RNA Nucleotide Strands From SARS-CoV-2 Variants and Subvariants: A Step Forward in the Definition of "Raman Genome".Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mechanism and key RNA determinants of SARS-CoV-2 Nsp1-induced endonucleolytic cleavage of mRNA.bioRxiv : the preprint server for biology · 2026Article
- Targeting SARS-CoV-2 Non-Structural Proteins: A Blueprint for Next-Generation Small-Molecule Coronavirus Antivirals.Pharmaceutics · 2026Review
- Decoding the Structural Complexity of Viral RNAs with SHAPE to Guide Antiviral Therapeutics.Viruses · 2026Review
- Structure and sequence characteristics of 5'-stem-loop 1 modulate the escape from nsp1-mediated repression in SARS-CoV-2 variants.Nucleic acids research · 2026Article
- Strategic variations in sarbecovirus and merbecovirus Nsp1 linker regions for translation inhibition.Nucleic acids research · 2026Article
- Predicting small molecule-RNA interactions without RNA tertiary structures.Nature biotechnology · 2026Article
- Integrative In Silico and In Vitro Screening of Low Molecular Weight Compounds Targeting SARS-CoV-2 RNA Elements.Chembiochem : a European journal of chemical biology · 2025Article
- "Fertile" Mutations in SARS-CoV-2 RNA More Frequently Occurred in Hairpin Loops That Determine Virus Evolution.APMIS : acta pathologica, microbiologica, et immunologica Scandinavica · 2025Article
- Crystallographic fragment screening against SARS-CoV-2 nonstructural protein 1 using the F2X-Entry Screen and a newly developed fragment library.Acta crystallographica. Section D, Structural biology · 2025Article
- A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation.Nature communications · 2025Article
- Antisense oligonucleotides targeting the SARS-CoV-2 nucleocapsid gene decrease viral titers in hamsters.Molecular therapy. Nucleic acids · 2025Article
- Post-transcriptional control of KRAS: functional roles of 5'UTR RNA G-quadruplexes, long noncoding RNA, and hnRNPA1.Nucleic acids research · 2025Article
- Targeting the SARS-CoV-2 RNA Translation Initiation Element SL1 by Molecules of Low Molecular Weight.Journal of the American Chemical Society · 2025Article
- PGLYRP2 drives hepatocyte-intrinsic innate immunity by trapping and clearing hepatitis B virus.The Journal of clinical investigation · 2025Article
- The differential effect of SARS-CoV-2 NSP1 on mRNA translation and stability reveals new insights linking ribosome recruitment, codon usage, and virus evolution.Nucleic acids research · 2025Article
- The transcriptional and translational landscape of HCoV-OC43 infection.PLoS pathogens · 2025Article
- IsomiRome analysis reveals dysregulation of 5' isomiRs during SARS-CoV-2 infection.Computational and structural biotechnology journal · 2025Article
- The role of intrinsically disordered regions of SARS-CoV-2 nucleocapsid and non-structural protein 1 proteins.Frontiers in chemistry · 2025Review
20 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.