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 (Aedes aegypti; Haemagogus leucocelaenus) 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 in vitro against both the vaccine strain (YFV-17D) and a viscerotropic clinical YFV isolate (DakH1279) concomitantly with low cellular cytotoxicity and no notable mitochondrial toxicity. In vivo, 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.