Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

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黄热病毒（Yellow fever virus, YFV）隶属于黄病毒科（Flaviviridae）。近年来，巴西毗邻城市区域的丛林型黄热（Yellow fever, YF）病例数呈爆发式增长。鉴于该病毒感染致死率极高且暂无获批抗病毒疗法，亟需发掘可用于应对黄热病毒暴发的治疗方案。对临床获批药物进行再利用，是应对公共卫生突发事件研发抗病毒药物的最快路径。 已有研究显示，寨卡病毒（Zika virus, ZIKV）、登革病毒（Dengue virus, DENV）等其他黄病毒对索非布韦（sofosbuvir）敏感——该药物是一款获批用于治疗丙型肝炎病毒（hepatitis C virus, HCV）感染的临床用药。 本研究数据表明，索非布韦可通过结合黄热病毒RNA聚合酶上负责核苷酸结合的保守氨基酸残基，实现与该酶的靶向结合。该药物可在人肝癌细胞中抑制黄热病毒疫苗株与野生株的复制，半数有效浓度（EC50）约为5 μM。此外，索非布韦可使感染黄热病毒的新生瑞士小鼠及成年I型干扰素受体敲除小鼠（A129-/-）免于死亡，并缓解其体重下降。 鉴于索非布韦在人体中具有良好的安全性，且在体外实验及小鼠模型中展现出显著的抗病毒活性，其有望成为黄热治疗的新型候选方案。 关键词：黄热病毒；黄热；抗病毒；索非布韦