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

基本信息

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
项目类别：
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

项目摘要

(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.

（在此处输入文本，这是您的申请的新摘要信息。本部分文本不得超过 30 行）在此应用中，我们提出了一种多学科方法来进行识别和进一步针对 DENV 丝氨酸蛋白酶（DENV 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，我们建议鉴定病毒 NS3 蛋白酶的新抑制剂和通过高通量筛选 (HTS) 和通过阻断 NS3/NS5 相互作用的化合物虚拟筛选。迄今为止，已鉴定出一系列新颖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，以获得有效和选择性药物样先导分子。在目标 2 中，一种新型且有效的抗病毒药物：我们名为 7DA6MEPN 的靶向 NS5 RdRP 已被确定可以抑制 DENV 复制。 7-脱氮杂-6-甲基嘌呤核糖核苷的其他类似物将是合成并评价以进一步提高该药物的疗效和治疗指数有前途的抗病毒剂。在目标 3 中，根据目标 1 鉴定和合成了化合物 2 将通过体外酶测定进一步评估抑制效力（IC50 值）、细胞毒性测定（CC50 值）、基于报告复制子以及病毒哺乳动物细胞培养物中的感染性测定（EC50）。选定的化合物显示 nM 范围内的抑制将通过 ADME/TOX 测定进行分析。