{"doi":"10.1128/aac.01039-24","title":"Oral pharmacokinetics and efficacy of oral phospholipid remdesivir nucleoside prodrugs against SARS-CoV-2 in mice","abstract":"ABSTRACT Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1- O -octadecyl-2- O -benzyl- sn -glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo . Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern.","journal":"Antimicrobial Agents and Chemotherapy","year":2024,"id":456457,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.947,"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":553827,"name":"James R. Beadle","orcid":"0000-0002-2690-6287","position":1,"is_corresponding":false},{"id":842500,"name":"Jeremy Ardanuy","orcid":"0000-0003-3886-427X","position":2,"is_corresponding":false},{"id":249772,"name":"Alex E. Clark","orcid":"0000-0003-1687-416X","position":3,"is_corresponding":false},{"id":1225135,"name":"Victoria Rhodes","orcid":"0000-0002-6638-5981","position":4,"is_corresponding":false},{"id":106549,"name":"Aaron F. Garretson","orcid":"0000-0003-3855-4482","position":5,"is_corresponding":false},{"id":554951,"name":"Joyce Murphy","orcid":null,"position":6,"is_corresponding":false},{"id":554949,"name":"Nadejda Valiaeva","orcid":null,"position":7,"is_corresponding":false},{"id":294612,"name":"Robert T. Schooley","orcid":"0000-0002-2498-8426","position":8,"is_corresponding":false},{"id":218418,"name":"Matthew B. Frieman","orcid":"0000-0003-0107-0775","position":9,"is_corresponding":false},{"id":553831,"name":"Karl Y. Hostetler","orcid":"0000-0002-1155-2885","position":10,"is_corresponding":false},{"id":103778,"name":"Aaron F. Carlin","orcid":"0000-0002-1669-8066","position":0,"is_corresponding":true}],"reference_count":13,"raw_metadata":null,"created_at":"2026-07-19T02:03:27.785212Z","pmid":"39240093","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":[]}