Project 4 - Influenza - UAB

项目 4 - 流感 - UAB

基本信息

批准号：
10380669
负责人：
RICHARD J. WHITLEY
金额：
$ 93.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380669
关键词：
Address Adult Animal Model Antiviral Agents Antiviral Therapy Avian Influenza A Virus Binding Biochemical Biological Assay Biological Availability California Chemicals Chemistry Child Clinical Collection Combination Drug Therapy Complex Coupled Data Development Drug Kinetics Drug usage Engineering Epidemic Epithelial Cells Ferrets Goals Human Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A Virus, H7N9 Subtype Influenza B Virus Institutes Japan Lead Maps Maximum Tolerated Dose Modeling Molecular Mus Neuraminidase inhibitor Oral Periodicity Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Polyadenylation Polymerase Predisposition Property Publishing RNA chemical synthesis RNA-Directed RNA Polymerase Research Resistance Resistance development Science Therapeutic Viral Physiology Virus Virus Inhibitors Virus Replication airway epithelium analog clinical development design drug development drug discovery effective therapy efficacy evaluation efficacy study experience experimental study fitness follow-up global health in vivo in vivo evaluation influenza infection influenza virus strain influenzavirus lead optimization new therapeutic target novel programs public-private partnership resistance mutation resistant strain scaffold targeted agent targeted nucleases

项目摘要

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.

概括该项目的总体目标是确定靶向病毒复制的新疗法。全球年度影响和周期性流行病的健康负担以及鸟类的出现诸如H5NX和H7N9之类的流感病毒强调了对新有效治疗的迫切需求。主要对治疗在美国影响影响的当前药物的关注是抗药性突变的发展否定了治疗益处。发表的证据和临床经验都强烈表明针对影响力依赖RNA RNA聚合酶（RDRP）复合物是抗病毒软件的一种理性方法治疗。该综合体负责许多病毒功能，包括5´帽识别，内核分解裂解，RNA合成和聚腺苷酸化提供多个功能域作为抗病毒的靶标药物疗法和联合疗法。代理可以针对不同的功能，理论上可以减少最小化电阻的发展，因为电阻突变可能会降低RDRP的保真度。靶向核酸内切酶域的一种口服剂Baloxavir已显示出简单的影响力的效率并最近在日本批准治疗成人和儿童的影响力。第二个口服代理 5´盖结合结构域Pimodivir在简单的流感中显示了抗病毒活性，并且正在前进在临床发展中。针对聚合酶活性的第三个口服剂favipiravir已批准日本用于治疗未被神经氨酸酶抑制剂抑制的新型影响者。我们最近确定了通过抑制RDRP功能的协作公共合作伙伴关系，几个潜在的分子。这研究团队提供药物化学专业知识，后续测定和体内经验将活性命中转化为铅化合物，并承诺产生新的高度活性分子靶向RDRP复合物。