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Discovery of a 2′-Fluoro,2′-Bromouridine Phosphoramidate Prodrug Exhibiting Anti-Yellow Fever Virus Activity in Culture and in Mice
- Source :
- Microorganisms, Vol 10, Iss 11, p 2098 (2022)
- Publication Year :
- 2022
- Publisher :
- MDPI AG, 2022.
-
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.
Details
- Language :
- English
- ISSN :
- 20762607
- Volume :
- 10
- Issue :
- 11
- Database :
- Directory of Open Access Journals
- Journal :
- Microorganisms
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.b7afa49fb6e74c87b2b2be789d66b3e8
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/microorganisms10112098