{"doi":"10.1101/2021.09.09.459641","title":"Targeting Stem-loop 1 of the SARS-CoV-2 5’UTR to suppress viral translation and Nsp1 evasion","abstract":"SARS-CoV-2 is a highly pathogenic virus that evades anti-viral 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 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 SL1 region of the SARS-CoV-2 5’ UTR is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides (ASOs) inhibits viral translation and makes SARS-CoV-2 5’ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration. 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215179,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":550806,"name":"Pietro Fontana","orcid":"0000-0003-3215-3784","position":1,"is_corresponding":false},{"id":635449,"name":"Valerie Leger","orcid":null,"position":2,"is_corresponding":false},{"id":634142,"name":"Ying Zhang","orcid":"0000-0002-1116-2182","position":3,"is_corresponding":false},{"id":250510,"name":"Tian‐Min Fu","orcid":"0000-0002-6281-1752","position":4,"is_corresponding":false},{"id":253642,"name":"Judy Lieberman","orcid":"0000-0002-6200-4715","position":5,"is_corresponding":false},{"id":98620,"name":"Lee Gehrke","orcid":"0000-0002-9387-8212","position":6,"is_corresponding":false},{"id":473412,"name":"Ming Shi","orcid":"0000-0003-0527-0061","position":7,"is_corresponding":false},{"id":473409,"name":"Longfei Wang","orcid":"0000-0002-8090-0935","position":8,"is_corresponding":false},{"id":228831,"name":"Hao Wu","orcid":"0000-0002-7281-8579","position":9,"is_corresponding":false},{"id":474275,"name":"Setu M. Vora","orcid":null,"position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-18T23:52:51.201033Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}