Targeting human respiratory syncytial virus transcription anti-termination factor M2-1 to inhibit in vivo viral replication.
Targeting human respiratory syncytial virus transcription anti-termination factor M2-1 to inhibit in vivo viral replication.
复制标题
靶向人呼吸道合胞病毒转录抗终止因子M2-1抑制体内病毒复制
DOI：
10.1038/srep25806
复制
发表时间：
2016-05-19
影响因子：
4.6
通讯作者：
Altmeyer R
中科院分区：
文献类型：
--
作者：
Bailly B;Richard CA;Sharma G;Wang L;Johansen L;Cao J;Pendharkar V;Sharma DC;Galloux M;Wang Y;Cui R;Zou G;Guillon P;von Itzstein M;Eléouët JF;Altmeyer R
人呼吸道合胞病毒（hRSV）是婴儿、老年人和免疫功能低下个体急性下呼吸道感染的主要原因。到目前为止，没有特定的抗病毒药物可用于治疗或预防这种疾病。在这里，我们报告说，Smoothened受体（Smo）拮抗剂环巴胺作为一种有效的和选择性的抑制剂，在体外和体内的hRSV复制。环巴胺通过一种新的非Smo依赖性机制抑制hRSV。它通过降低病毒抗终止因子M2-1的表达水平特异性地损害hRSV RNA依赖性RNA聚合酶复合物的功能。M2-1中的单个R151 K突变足以在体外赋予病毒对环巴胺的抗性，并且环巴胺能够降低hRSV感染小鼠模型中的病毒滴度，这证实了这些发现的相关性。我们的研究结果为开发未来抗hRSV感染的疗法开辟了一条新途径。
Human respiratory syncytial virus (hRSV) is a leading cause of acute lower respiratory tract infection in infants, elderly and immunocompromised individuals. To date, no specific antiviral drug is available to treat or prevent this disease. Here, we report that the Smoothened receptor (Smo) antagonist cyclopamine acts as a potent and selective inhibitor of in vitro and in vivo hRSV replication. Cyclopamine inhibits hRSV through a novel, Smo-independent mechanism. It specifically impairs the function of the hRSV RNA-dependent RNA polymerase complex notably by reducing expression levels of the viral anti-termination factor M2-1. The relevance of these findings is corroborated by the demonstration that a single R151K mutation in M2-1 is sufficient to confer virus resistance to cyclopamine in vitro and that cyclopamine is able to reduce virus titers in a mouse model of hRSV infection. The results of our study open a novel avenue for the development of future therapies against hRSV infection.