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

Proc Natl Acad Sci U S A. 2022 Mar 1;119(9):e2117198119. doi: 10.1073/pnas.2117198119.


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.

Keywords: SARS-CoV-2; therapeutic; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics*
  • Animals
  • Base Sequence
  • Chlorocebus aethiops
  • HEK293 Cells
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / genetics
  • Humans
  • Immune Evasion / drug effects
  • Immune Evasion / genetics*
  • Mice, Transgenic
  • Models, Biological
  • Oligonucleotides, Antisense / pharmacology
  • Protein Biosynthesis* / drug effects
  • SARS-CoV-2 / drug effects
  • SARS-CoV-2 / genetics*
  • Vero Cells
  • Viral Nonstructural Proteins / genetics*
  • Virus Replication / drug effects


  • 5' Untranslated Regions
  • NSP1 protein, SARS-CoV-2
  • Oligonucleotides, Antisense
  • Viral Nonstructural Proteins