Discovery of a 2'-Fluoro,2'-Bromouridine Phosphoramidate Prodrug Exhibiting Anti-Yellow Fever Virus Activity in Culture and in Mice

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, t...

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Published in:Microorganisms (Basel) 2022-10, Vol.10 (11), p.2098
Main Authors: LeCher, Julia C, Zandi, Keivan, Costa, Vivian Vasconcelos, Amblard, Franck, Tao, Sijia, Patel, Dharmeshkumar, Lee, Sujin, da Silva Santos, Felipe Rocha, Goncalves, Matheus Rodrigues, Queroz-Junior, Celso Martins, Marim, Fernanda Martins, Musall, Katie, Goh, Shu Ling, McBrayer, Tamara, Downs-Bowen, Jessica, De, Ramyani, Azadi, Niloufar, Kohler, James, Teixeira, Mauro Martins, Schinazi, Raymond F
Format: Article
Language:English
Subjects:
A129 mouse model
Animal models
Antiviral agents
Blood
Blood banks
Care and treatment
Chemical compounds
Comparative analysis
Cytotoxicity
Epidemics
Fever
flavivirus
Hepatitis C
Identification and classification
Liver
Macrophages
Microscopy
NMR
Nuclear magnetic resonance
Nucleoside analogs
Nucleosides
Organophosphorus compounds
Pharmacology
Physiological aspects
Prediction models
Prodrugs
RNA polymerase
Spheroids
Toxicity
Vector-borne diseases
Viruses
Yellow fever
yellow fever virus
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Summary: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.
ISSN:2076-2607
2076-2607
DOI:10.3390/microorganisms10112098