{"doi":"10.1101/2023.06.27.546784","title":"Efficacy of the oral nucleoside prodrug GS-5245 (Obeldesivir) against SARS-CoV-2 and coronaviruses with pandemic potential","abstract":"Abstract Despite the wide availability of several safe and effective vaccines that can prevent severe COVID-19 disease, the emergence of SARS-CoV-2 variants of concern (VOC) that can partially evade vaccine immunity remains a global health concern. In addition, the emergence of highly mutated and neutralization-resistant SARS-CoV-2 VOCs such as BA.1 and BA.5 that can partially or fully evade ( 1 ) many therapeutic monoclonal antibodies in clinical use underlines the need for additional effective 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 RNA-dependent viral RNA polymerase (RdRp). Importantly, we show that GS-5245 is broadly potent in vitro against alphacoronavirus HCoV-NL63, severe acute respiratory syndrome coronavirus (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 in vitro and highly effective as antiviral therapy in mouse models of SARS-CoV, SARS-CoV-2 (WA/1), MERS-CoV and Bat-CoV RsSHC014 pathogenesis. In all these models of divergent coronaviruses, we observed protection and/or significant reduction of disease metrics such as weight loss, lung viral replication, acute lung injury, and degradation in pulmonary function in GS-5245-treated mice compared to vehicle controls. Finally, we demonstrate that GS-5245 in combination with the main protease (M pro ) inhibitor nirmatrelvir had increased efficacy in vivo against SARS-CoV-2 compared to each single agent. Altogether, our data supports the continuing clinical evaluation of GS-5245 in humans infected with COVID-19, including as part of a combination antiviral therapy, especially in populations with the most urgent need for more efficacious and durable interventions.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":390268,"datarank":0.5580262967107679,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.17328389309153736,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.17328389309153736,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":9,"citers_with_citation_signal":7,"citers_with_endowment":7,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","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":894117,"name":"Mark R. Zweigart","orcid":"0000-0001-5765-3203","position":2,"is_corresponding":false},{"id":105603,"name":"Kendra L. Gully","orcid":"0000-0001-5742-2341","position":3,"is_corresponding":false},{"id":623529,"name":"Gabriela De la Cruz","orcid":"0000-0002-6019-5853","position":4,"is_corresponding":false},{"id":105114,"name":"Ariane J. Brown","orcid":null,"position":5,"is_corresponding":false},{"id":109139,"name":"Lily E. Adams","orcid":"0000-0001-7780-9973","position":6,"is_corresponding":false},{"id":1064449,"name":"Nicholas Catanzaro","orcid":"0000-0002-0210-8440","position":7,"is_corresponding":false},{"id":105503,"name":"Boyd L. Yount","orcid":"0000-0002-6099-8429","position":8,"is_corresponding":false},{"id":355498,"name":"Thomas J. Baric","orcid":"0009-0005-8682-0740","position":9,"is_corresponding":false},{"id":376982,"name":"Michael L. Mallory","orcid":"0000-0003-0768-572X","position":10,"is_corresponding":false},{"id":1162052,"name":"Helen Conrad","orcid":null,"position":11,"is_corresponding":false},{"id":894611,"name":"Samantha R. May","orcid":null,"position":12,"is_corresponding":false},{"id":816366,"name":"Stephanie Dong","orcid":"0000-0002-0318-5261","position":13,"is_corresponding":false},{"id":894610,"name":"D. Trevor Scobey","orcid":null,"position":14,"is_corresponding":false},{"id":105115,"name":"Stephanie A. Montgomery","orcid":"0000-0001-8012-5302","position":15,"is_corresponding":false},{"id":97929,"name":"Jason K. Perry","orcid":"0000-0001-5492-0652","position":16,"is_corresponding":false},{"id":105117,"name":"Darius Babusis","orcid":"0000-0001-5599-1671","position":17,"is_corresponding":false},{"id":805289,"name":"Kimberly T. Barrett","orcid":"0000-0003-4128-8437","position":18,"is_corresponding":false},{"id":1162053,"name":"Anh‐Hoa Nguyen","orcid":null,"position":19,"is_corresponding":false},{"id":1027297,"name":"Anh-Quan Nguyen","orcid":"0009-0003-9348-2060","position":20,"is_corresponding":false},{"id":805979,"name":"Rao Kalla","orcid":null,"position":21,"is_corresponding":false},{"id":547001,"name":"Roy Bannister","orcid":"0000-0002-6311-1440","position":22,"is_corresponding":false},{"id":105311,"name":"John P. Bilello","orcid":"0000-0003-4327-1727","position":23,"is_corresponding":false},{"id":105123,"name":"Joy Y. Feng","orcid":"0000-0003-4837-1911","position":24,"is_corresponding":false},{"id":105124,"name":"Tomáš Cihlář","orcid":"0000-0001-6840-0885","position":25,"is_corresponding":false},{"id":5952,"name":"Ralph S. Baric","orcid":"0000-0001-6827-8701","position":26,"is_corresponding":false},{"id":607946,"name":"Richard L. Mackman","orcid":"0000-0001-8861-7205","position":27,"is_corresponding":false},{"id":105112,"name":"Alexandra Schäfer","orcid":null,"position":28,"is_corresponding":false},{"id":5953,"name":"Timothy P. Sheahan","orcid":"0000-0001-9181-2183","position":29,"is_corresponding":false},{"id":105498,"name":"David R. Martinez","orcid":"0000-0002-2940-8961","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:32.854511Z","pmid":"37425890","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":[]}