Project 4 - Influenza - UAB

摘要 该项目的总体目标是确定针对流感病毒复制的新疗法。《环球报》 每年的流感感染和周期性流行加上禽类的出现造成的健康负担 H5NX和H7N9等流感病毒突显了对新的有效治疗方法的迫切需要。一个主要的 美国目前用于治疗流感的药物令人担忧的是耐药性突变的发展 这就否定了治疗的好处。已发表的证据和临床经验都有力地表明，靶向 流感病毒依赖RNA聚合酶(RdRp)复合体是一种合理的抗病毒方法 心理治疗。这个复合体负责许多病毒功能，包括5‘帽识别、核酸内切 作为抗病毒靶点的切割、RNA合成和提供多个功能结构域的多聚腺苷 药物治疗和联合治疗。代理可以针对不同的功能，从理论上减少 尽量减少耐药性的产生，因为耐药性突变可能会降低RdRp的保真度。 一种针对核酸内切酶结构域的口服药物巴洛沙韦已显示出对简单流感的疗效 最近在日本被批准用于治疗成人和儿童流感。第二种口服剂靶向 5‘帽结合结构域，匹莫地韦，已经在简单的流感中显示出抗病毒活性，并且正在进展 在临床开发中。针对聚合酶活性的第三种口服药物法韦拉韦已于#年获得批准。 日本用于治疗未被神经氨酸酶抑制剂抑制的新型流感病毒株。我们最近确认了 通过公私合作伙伴关系抑制RdRp功能的几个有效分子。这 研究团队提供药物化学专业知识、后续分析和活体经验 将活性物质转化为先导化合物，并有望产生新的高活性分子类别 瞄准RdRp建筑群。

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.