Open AccessTargeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion
Author(s) -
Setu M. Vora,
Pietro Fontana,
Tianyang Mao,
Valerie Leger,
Ying Zhang,
TianMin Fu,
Judy Lieberman,
Lee Gehrke,
Ming Shi,
Long Wang,
Akiko Iwasaki,
Hao Wu
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2117198119
Subject(s) - virology , viral replication , translation (biology) , untranslated region , biology , three prime untranslated region , covid-19 , evasion (ethics) , stem loop , computational biology , genetics , medicine , virus , rna , gene , messenger rna , immune system , disease , infectious disease (medical specialty) , pathology
Significance The COVID-19 pandemic and the ever-evolving variants of SARS-CoV-2 are taking a toll on human health. Despite the successful rollout of vaccines, effective therapies are still urgently needed. Our studies here showing that Nsp1 selectively blocks translation of host but not viral proteins by proper coordination of its N- and C-terminal domains to advance our understanding on SARS-CoV-2 pathogenesis. Our finding that stem-loop 1, a highly conserved sequence in the SARS-CoV-2 5′ UTR, is necessary and sufficient for bypassing Nsp1-mediated shutdown led to the design of antisense oligonucleotides targeting this sequence that make viral translation susceptible to Nsp1 shutdown, interfere with viral replication, and protect SARS-CoV-2–infected mice. This strategy of turning SARS-CoV-2’s own virulence against itself could be harnessed therapeutically.