Development of Antiviral Therapeutics for Dengue: Inhibitors of Viral Protease

登革热抗病毒治疗药物的开发：病毒蛋白酶抑制剂

• 批准号: 7644685
• 负责人: Radhakrishnan Padmanabhan
• 金额: $ 64.55万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644685
• 关键词: 6-methylpurine; Antiviral Agents; Area; Binding; Biochemical; Biological Assay; Categories; Cell Culture Techniques; Cell Line; Cells; Culicidae; Data; Dengue; Dengue Virus; Development; Development Plans; Developmental Therapeutics Program; Docking; Enzymes; Epidemic; Family; Flaviviridae; Hand; Homology Modeling; Human; In Vitro; Inhibitory Concentration 50; Label; Laboratories; Lead; Libraries; Life; Mammalian Cell; Methods; Molecular; Molecular Models; Molecular Probes; Morbidity - disease rate; National Cancer Institute; National Institute of Allergy and Infectious Disease; Peptide Hydrolases; Pharmaceutical Preparations; Population; Protease Inhibitor; RNA-Directed RNA Polymerase; Replicon; Reporter; Research; Ribonucleosides; Risk; Screening procedure; Series; Serine Protease; Structure; System; Therapeutic; Therapeutic Index; Vaccines; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; West Nile virus; analog; base; chemical synthesis; combinatorial chemistry; cytotoxicity; dengue virus NS3; high throughput screening; improved; indexing; inhibitor/antagonist; member; molecular modeling; mortality; novel; nucleoside triphosphate; pathogen; pre-clinical; product development; repository; scaffold; scale up; small molecule; viral RNA; virtual

(Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text) In this application, we propose a multi-disciplinary approach for identification and further development of lead molecules already in hand against DENV serine protease (DENV NSSpro) and RNA-dependent RNA polymerase (DENV RdRP). The product development plan would involve completion of following three specific aims and milestones. In aim 1, we propose to identify new inhibitors of the viral NS3 protease and compounds that block NS3/NS5 interaction by high throughput screening (HTS) and by virtual screening. The novel series of compounds have been have been identified to date as promising protease inhibitors. Compounds will be further optimized by iterative medicinal and combinatorial chemistry, molecular modeling, to obtain potent and selective drug-like lead molecules. In aim 2, a novel and potent antiviral agent: that we termed 7DA6MEPN that targets the NS5 RdRP has been identified to inhibit DENV replication. Additional analogues of 7-deaza-6-methylpurine ribonucleoside will be synthesized and evaluated to further improve the efficacy and therapeutic index of this promising antiviral agent. In aim 3, compounds identified and synthesized under aims 1 and 2 will be further evaluated for inhibitory potency by in vitro enzyme assays (IC50 values), cytotoxicity assays (CC50 values), reporter replicon-based as well as virus infectivity assays (EC50) in mammalian cell culture. Selected compounds showing inhibition in the nM range will be analyzed by ADME/TOX assays.

（在此输入文本，它是应用程序的新摘要信息。本节 不得超过30行文本） 在这个应用中，我们提出了一个多学科的方法来识别，并进一步 已经开发了针对DENV丝氨酸蛋白酶（DENV）的先导分子 NSSpro）和RNA依赖性RNA聚合酶（DENV RdRP）。产品 发展计划将涉及完成以下三个具体目标， 里程碑在目标1中，我们提出鉴定病毒NS 3蛋白酶的新抑制剂， 通过高通量筛选（HTS）和通过 虚拟筛选到目前为止，已经鉴定了一系列新的化合物 作为有前途的蛋白酶抑制剂。化合物将通过迭代进一步优化 药物和组合化学，分子建模，以获得有效的， 选择性药物样铅分子。在目标2中，一种新的有效的抗病毒剂：我们 称为7 DA 6 MEPN的靶向NS 5 RdRP已被鉴定为抑制DENV 复制的7-脱氮-6-甲基嘌呤核糖核苷的其他类似物将在本文中公开。 合成和评价，以进一步提高这种药物的疗效和治疗指数， 很有前途的抗病毒剂在目标3中，根据目标1鉴定和合成的化合物 通过体外酶测定法（IC 50）进一步评价化合物1和2的抑制效力 值）、细胞毒性测定（CC 50值）、基于报告复制子的以及病毒 哺乳动物细胞培养物中的感染性测定（EC 50）。所选化合物显示 将通过ADME/TOX测定分析nM范围内的抑制。