{"doi":"10.1126/scitranslmed.adj4504","title":"The oral nucleoside prodrug GS-5245 is efficacious against SARS-CoV-2 and other endemic, epidemic, and enzootic coronaviruses","abstract":"Despite the wide availability of several safe and effective vaccines that prevent severe COVID-19, the persistent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) that can evade vaccine-elicited immunity remains a global health concern. In addition, the emergence of SARS-CoV-2 VOCs that can evade therapeutic monoclonal antibodies underscores the need for additional, variant-resistant treatment strategies. Here, we characterize the antiviral activity of GS-5245, obeldesivir (ODV), an oral prodrug of the parent nucleoside GS-441524, which targets the highly conserved viral RNA-dependent RNA polymerase (RdRp). We show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, SARS-CoV, SARS-CoV–related bat-CoV RsSHC014, Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV-2 WA/1, and the highly transmissible SARS-CoV-2 BA.1 Omicron variant. Moreover, in mouse models of SARS-CoV, SARS-CoV-2 (WA/1 and Omicron B1.1.529), MERS-CoV, and bat-CoV RsSHC014 pathogenesis, we observed a dose-dependent reduction in viral replication, body weight loss, acute lung injury, and pulmonary function with GS-5245 therapy. Last, we demonstrate that a combination of GS-5245 and main protease (M pro ) inhibitor nirmatrelvir improved outcomes in vivo against SARS-CoV-2 compared with the single agents. Together, our data support the clinical evaluation of GS-5245 against coronaviruses that cause or have the potential to cause human disease.","journal":"Science Translational Medicine","year":2024,"id":424180,"datarank":0.8882673161972592,"base_score":3.1354942159291497,"endowment":3.1354942159291497,"self_citation_contribution":0.47032413238937254,"citation_network_contribution":0.41794318380788664,"self_endowment_contribution":0.47032413238937254,"citer_contribution":0.41794318380788664,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":15,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":805286,"name":"Fernando R. Moreira","orcid":"0000-0002-6606-7668","position":1,"is_corresponding":false},{"id":1064449,"name":"Nicholas Catanzaro","orcid":"0000-0002-0210-8440","position":2,"is_corresponding":false},{"id":950295,"name":"Meghan V. Diefenbacher","orcid":"0000-0002-8818-3686","position":3,"is_corresponding":false},{"id":894117,"name":"Mark R. Zweigart","orcid":"0000-0001-5765-3203","position":4,"is_corresponding":false},{"id":105603,"name":"Kendra L. Gully","orcid":"0000-0001-5742-2341","position":5,"is_corresponding":false},{"id":623529,"name":"Gabriela De la Cruz","orcid":"0000-0002-6019-5853","position":6,"is_corresponding":false},{"id":105114,"name":"Ariane J. Brown","orcid":null,"position":7,"is_corresponding":false},{"id":109139,"name":"Lily E. Adams","orcid":"0000-0001-7780-9973","position":8,"is_corresponding":false},{"id":105503,"name":"Boyd L. Yount","orcid":"0000-0002-6099-8429","position":9,"is_corresponding":false},{"id":355498,"name":"Thomas J. Baric","orcid":"0009-0005-8682-0740","position":10,"is_corresponding":false},{"id":376982,"name":"Michael L. Mallory","orcid":"0000-0003-0768-572X","position":11,"is_corresponding":false},{"id":1162052,"name":"Helen Conrad","orcid":null,"position":12,"is_corresponding":false},{"id":894611,"name":"Samantha R. May","orcid":null,"position":13,"is_corresponding":false},{"id":816366,"name":"Stephanie Dong","orcid":"0000-0002-0318-5261","position":14,"is_corresponding":false},{"id":894610,"name":"D. Trevor Scobey","orcid":null,"position":15,"is_corresponding":false},{"id":1220494,"name":"Cameron Nguyen","orcid":"0000-0003-2374-438X","position":16,"is_corresponding":false},{"id":105115,"name":"Stephanie A. Montgomery","orcid":"0000-0001-8012-5302","position":17,"is_corresponding":false},{"id":97929,"name":"Jason K. Perry","orcid":"0000-0001-5492-0652","position":18,"is_corresponding":false},{"id":105117,"name":"Darius Babusis","orcid":"0000-0001-5599-1671","position":19,"is_corresponding":false},{"id":805289,"name":"Kimberly T. Barrett","orcid":"0000-0003-4128-8437","position":20,"is_corresponding":false},{"id":1162053,"name":"Anh‐Hoa Nguyen","orcid":null,"position":21,"is_corresponding":false},{"id":1027297,"name":"Anh-Quan Nguyen","orcid":"0009-0003-9348-2060","position":22,"is_corresponding":false},{"id":805979,"name":"Rao Kalla","orcid":null,"position":23,"is_corresponding":false},{"id":547001,"name":"Roy Bannister","orcid":"0000-0002-6311-1440","position":24,"is_corresponding":false},{"id":105123,"name":"Joy Y. Feng","orcid":"0000-0003-4837-1911","position":25,"is_corresponding":false},{"id":105124,"name":"Tomáš Cihlář","orcid":"0000-0001-6840-0885","position":26,"is_corresponding":false},{"id":5952,"name":"Ralph S. 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Martinez","orcid":"0000-0002-2940-8961","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:58:07.191194Z","pmid":"38776389","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":[]}