{"doi":"10.3390/microorganisms10112098","title":"Discovery of a 2′-Fluoro,2′-Bromouridine Phosphoramidate Prodrug Exhibiting Anti-Yellow Fever Virus Activity in Culture and in Mice","abstract":"Yellow fever virus (YFV) is a potentially lethal, zoonotic, blood-borne flavivirus transmitted to humans and non-human primates by mosquitoes. Owing to multiple deadly epidemics, the WHO classifies YFV as a \"high impact, high threat disease\" with resurgent epidemic potential. At present, there are no approved antiviral therapies to combat YFV infection. Herein we report on 2'-halogen-modified nucleoside analogs as potential anti-YFV agents. Of 11 compounds evaluated, three showed great promise with low toxicity, high intracellular metabolism into the active nucleoside triphosphate form, and sub-micromolar anti-YFV activity. Notably, we investigated a 2'-fluoro,2'-bromouridine phosphate prodrug (C9), a known anti-HCV agent with good stability in human blood and favorable metabolism. Predictive modeling revealed that C9 could readily bind the active site of the YFV RdRp, conferring its anti-YFV activity. C9 displayed potent anti-YFV activity in primary human macrophages, 3D hepatocyte spheroids, and in mice. In an A129 murine model, shortly after infection, C9 significantly reduced YFV replication and protected against YFV-induced liver inflammation and pathology with no adverse effects. Collectively, this work identifies a potent new anti-YFV agent with strong therapeutic promise.","journal":"Microorganisms","year":2022,"id":268118,"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":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":244969,"name":"Keivan Zandi","orcid":"0000-0001-9728-5038","position":1,"is_corresponding":false},{"id":375883,"name":"Vivian Vasconcelos Costa","orcid":"0000-0002-0175-642X","position":2,"is_corresponding":false},{"id":314480,"name":"Franck Amblard","orcid":"0009-0002-6235-4050","position":3,"is_corresponding":false},{"id":248189,"name":"Sijia Tao","orcid":null,"position":4,"is_corresponding":false},{"id":432486,"name":"Dharmeshkumar Patel","orcid":"0000-0003-1601-256X","position":5,"is_corresponding":false},{"id":381121,"name":"Sujin Lee","orcid":"0000-0002-6692-6880","position":6,"is_corresponding":false},{"id":904761,"name":"Felipe Rocha da Silva Santos","orcid":"0000-0002-8392-1467","position":7,"is_corresponding":false},{"id":929757,"name":"Matheus Rodrigues Gonçalves","orcid":"0009-0008-0798-9778","position":8,"is_corresponding":false},{"id":930308,"name":"Celso Martins Queroz-Junior","orcid":null,"position":9,"is_corresponding":false},{"id":751394,"name":"Fernanda Martins Marim","orcid":"0000-0002-9778-554X","position":10,"is_corresponding":false},{"id":315996,"name":"Katie Musall","orcid":null,"position":11,"is_corresponding":false},{"id":900941,"name":"Shu Ling Goh","orcid":"0000-0001-8575-6103","position":12,"is_corresponding":false},{"id":315999,"name":"Tamara R. McBrayer","orcid":null,"position":13,"is_corresponding":false},{"id":314481,"name":"Jessica Downs-Bowen","orcid":"0000-0002-7472-033X","position":14,"is_corresponding":false},{"id":929758,"name":"Ramyani De","orcid":"0000-0001-5534-0705","position":15,"is_corresponding":false},{"id":930309,"name":"Niloufar Azadi","orcid":null,"position":16,"is_corresponding":false},{"id":694293,"name":"James J. Kohler","orcid":null,"position":17,"is_corresponding":false},{"id":375884,"name":"Mauro Martins Teixeira","orcid":"0000-0002-6944-3008","position":18,"is_corresponding":false},{"id":228075,"name":"Raymond F. Schinazi","orcid":"0000-0002-6688-3614","position":19,"is_corresponding":false},{"id":693450,"name":"Julia C. LeCher","orcid":"0000-0002-0056-176X","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T00:27:10.233250Z","pmid":"36363688","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":[]}