Project 4 - Influenza - UAB

项目 4 - 流感 - UAB

基本信息

批准号：
10115602
负责人：
RICHARD J. WHITLEY
金额：
$ 88.85万
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/10115602
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针对全球流感病毒复制的新疗法。每年流感感染和周期性流行病以及禽流感的出现造成的健康负担 H5NX 和 H7N9 等流感病毒凸显了对新有效治疗方法的迫切需要。对美国目前用于治疗流感的药物的担忧是耐药突变的发展已发表的证据和临床经验都强烈表明靶向治疗的效果。流感病毒RNA依赖性RNA聚合酶（RdRp）复合物是抗病毒的合理方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 合成和聚腺苷酸化提供多个功能域作为抗病毒靶标药物治疗和联合治疗可以针对不同的功能，从理论上讲，可以减少疾病的发生。最大限度地减少耐药性的发展，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的第二种口服药物。 5´帽结合域，匹莫迪韦，已在简单的流感中显示出抗病毒活性，并且正在推进第三种口服药物法匹拉韦（favipiravir）已在临床开发中获得批准，该药物针对聚合酶活性。日本我们最近发现了治疗不受神经氨酸酶抑制剂抑制的新型流感病毒株的方法。通过公私合作伙伴关系抑制 RdRp 功能的几种有效分子。研究团队提供药物化学专业知识、后续检测和体内经验将活性化合物转化为先导化合物，并有望产生新型高活性分子靶向 RdRp 复合物。