Abstract
Yellow fever virus (YFV) is a member of the Flaviviridae family. In Brazil, yellow fever (YF) cases have increased dramatically in sylvatic areas neighboring urban zones in the last few years. Because of the high lethality rates associated with infection and absence of any antiviral treatments, it is essential to identify therapeutic options to respond to YFV outbreaks. Repurposing of clinically approved drugs represents the fastest alternative to discover antivirals for public health emergencies. Other Flaviviruses, such as Zika (ZIKV) and dengue (DENV) viruses, are susceptible to sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Our data showed that sofosbuvir docks onto YFV RNA polymerase using conserved amino acid residues for nucleotide binding. This drug inhibited the replication of both vaccine and wild-type strains of YFV on human hepatoma cells, with EC50 values around 5 μM. Sofosbuvir protected YFV-infected neonatal Swiss mice and adult type I interferon receptor knockout mice (A129-/-) from mortality and weight loss. Because of its safety profile in humans and significant antiviral effects in vitro and in mice, Sofosbuvir may represent a novel therapeutic option for the treatment of YF. Key-words: Yellow fever virus; Yellow fever, antiviral; sofosbuvir
Highlights
Yellow fever virus (YFV) is a single-strand positive-sense RNA virus which belongs to the Flaviviridae family
We showed that sofosbuvir, clinically approved against hepatitis C, inhibits yellow fever virus replication in liver cell lines and animal models
Our pre-clinical results supports a second use of sofosbuvir against yellow fever
Summary
Yellow fever virus (YFV) is a single-strand positive-sense RNA virus which belongs to the Flaviviridae family. Yellow fever (YF) outbreaks were very common throughout the tropical world until the beginning of the 20th century, when vaccination and vector control limited the urban virus circulation [1]. Sylvatic and urban cycles of YFV transmission occur. Non-human primates are sylvatic reservoirs of jungle YFV and non-immunized humans entering the rain forest and those living in the ecotone (between preserved rain forest and urban area) are highly susceptible to YFV, which is transmitted by mosquitoes from Haemagogus and Sabethes genera [2]. The virus is usually brought to urban settings by viremic humans infected in the jungle [2]. The urban cycle involves transmission of the virus among humans by vectors like Aedes spp. mosquitoes [2]
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