Project 4 - Influenza - UAB

总结 该项目的总体目标是确定针对流感病毒复制的新疗法。全球 每年的流感感染和周期性流行病以及禽流感的出现对健康造成的负担 流感病毒，如H5NX和H7N9，突出了对新的有效治疗的迫切需要。主 在美国，目前用于治疗流感的药物存在耐药性突变的问题 否定了治疗效果。已发表的证据和临床经验都强烈表明， 流感病毒RNA依赖性RNA聚合酶（RdRp）复合物是一种合理抗病毒方法 疗法该复合物负责许多病毒功能，包括5 ′帽识别、核酸内切 切割、RNA合成和多聚腺苷酸化，提供多个功能结构域作为抗病毒药物的靶点， 药物治疗和联合治疗。代理可以针对不同的功能，理论上， 最小化耐药性的发展，因为耐药性突变可能会降低RdRp的保真度。 一种靶向核酸内切酶结构域的口服药物baloxavir已在单纯性流感中显示出疗效 最近在日本被批准用于治疗成人和儿童流感。第二口服剂靶向 5 ′帽结合结构域Pimodivir在简单的流感中显示出抗病毒活性， 在临床开发中。靶向聚合酶活性的第三种口服药物法匹拉韦已于2009年获得批准。 日本治疗不被神经氨酸酶抑制剂抑制的新型流感病毒株。我们最近发现 几个有效的分子通过合作的公私伙伴关系，抑制RdRp功能。这 研究团队提供药物化学专业知识，后续分析和体内经验， 将活性物质转化为先导化合物，并有望产生新型高活性分子， 以RdRp复合体为目标

SUMMARY The overall goal of this project is to identify new therapies that target influenza virus replication. The global health burden of annual influenza infections and periodic epidemics coupled with the emergence of avian influenza viruses, like H5NX and H7N9, highlight the urgent need for new effective treatments. A primary concern with the current drugs used to treat influenza in the U.S. is the development of resistance mutations that negate therapeutic benefit. Both published evidence and clinical experience suggest strongly that targeting the influenza virus RNA dependent RNA polymerase (RdRp) complex is a rational approach for antiviral therapy. This complex is responsible for many viral functions, including 5´ cap recognition, endonucleolytic cleavage, RNA synthesis, and polyadenylation providing multiple functional domains as targets for antiviral drug therapy and combination therapy. Agents can target the distinct functions and, theoretically, reduce the minimize development of resistance since resistance mutations would likely reduce the fidelity of the RdRp. One oral agent targeting the endonuclease domain, baloxavir, has shown efficacy in uncomplicated influenza and was recently approved in Japan for treating influenza in adults and children. A second oral agent targeting the 5´ cap binding domain, pimodivir, has shown antiviral activity in uncomplicated influenza and is advancing in clinical development. A third oral agent, favipiravir, targeting the polymerase activity has been approved in Japan for treating novel influenza strains not inhibited by neuraminidase inhibitors. We have recently identified several potent molecules through a collaborative public private partnership that inhibit RdRp functions. This research team provides the medicinal chemistry expertise, follow up assays, and in vivo experience to transform active hits into lead compounds and promises to yield new classes of highly active molecules that target the RdRp complex.