Combating yellow fever virus with 7-deaza-7-fluoro-2′-C-methyladenosine
Yellow fever virus (YFV) is a deadly zoonotic flavivirus endemic in tropical/sub-tropical Africa and South America transmitted by mosquito vector (<i>Aedes aegypti</i>; <i>Haemagogus leucocelaenus</i>) to humans and non-human primates. There are no approved antiviral agents for YFV. We previously identified 7-deaza-7-fluoro-2'-C-methyladenosine (DFA) with anti-YFV activity. Interestingly, DFA exhibits pan-activity in vitro against flaviviruses, such as dengue, Japanese encephalitis, Zika, and hepatitis C. This study aimed to expand DFA's anti-flavivirus profile. DFA exhibited potent sub-micromolar anti-YFV activity <i>in vitro</i> against both the vaccine strain (YFV-17D) and a viscerotropic clinical YFV isolate (DakH1279) concomitantly with low cellular cytotoxicity and no notable mitochondrial toxicity. <i>In vivo</i>, efficacy was assessed against both YFV-17DD and a human clinical isolate in A129 and AG129 mouse flavivirus infection models, respectively. DFA significantly reduced virus replication in the livers of YFV-infected mice and the hallmarks of YFV-induced liver damage, including alanine transaminase levels and indocyanine green clearance. Collectively, this work identifies DFA as a potent YFV inhibitor and lays the groundwork for further therapeutic development as a YFV and, potentially, pan-flavivirus therapeutic.
Authors
- Celso Martins Queroz-Junior
- Franck Amblard (ORCID: https://orcid.org/0009-0002-6235-4050)
- Mauro Martins Teixeira (ORCID: https://orcid.org/0000-0002-6944-3008)
- Dharmeshkumar Patel (ORCID: https://orcid.org/0000-0003-1601-256X)
- Leda Bassit (ORCID: https://orcid.org/0000-0001-9894-5587)
- Fernanda Martins Marim (ORCID: https://orcid.org/0000-0002-9778-554X)
- Keivan Zandi (ORCID: https://orcid.org/0000-0001-9728-5038)
- Sahar Rezaei
- Benjamin J. Burwitz (ORCID: https://orcid.org/0000-0001-7767-022X)
- Julia C. LeCher (ORCID: https://orcid.org/0000-0002-0056-176X)
- Niloufar Azadi
- Lauren N. Rust (ORCID: https://orcid.org/0000-0001-8585-466X)
- Ramyani De (ORCID: https://orcid.org/0000-0001-5534-0705)
- Vivian Vasconcelos Costa (ORCID: https://orcid.org/0000-0002-0175-642X)
- Raymond F. Schinazi (ORCID: https://orcid.org/0000-0002-6688-3614)
- Felipe Rocha da Silva Santos (ORCID: https://orcid.org/0000-0002-8392-1467)
- Sujin Lee (ORCID: https://orcid.org/0000-0002-6692-6880)
- Longhu Zhou
- Mohammad Salman (ORCID: https://orcid.org/0009-0007-5677-9219)
- Matheus Rodrigues Gonçalves (ORCID: https://orcid.org/0009-0008-0798-9778)
- Tamara R. McBrayer
- Justin Moua
Institutions
- Oregon National Primate Research Center (US)
- Universidade Federal de Minas Gerais (BR)
- Emory University (US)
- Oregon Health & Science University (US)
- Morpho (United States) (US)
- Children's Healthcare of Atlanta (US)
Publication Details
- Journal
- Antimicrobial Agents and Chemotherapy
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1128/aac.01889-24
- Citations
- 2
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- National Institutes of Health