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: 7932902
• 负责人: Radhakrishnan Padmanabhan
• 金额: $ 54.33万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932902
• 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.

(在此处输入文本，这是您的应用程序的新摘要信息。这一节 不得超过30行文本) 在这个应用中，我们提出了一种多学科的识别方法，并进一步 抗DENV丝氨酸蛋白酶(DENV)的铅分子研究进展 NSSpro)和依赖RNA的RNA聚合酶(DENV RdRP)。该产品 发展计划将包括完成以下三个具体目标和 里程碑。在目标1中，我们建议寻找新的病毒NS3蛋白水解酶抑制剂和 通过高通量筛选(HTS)和通过以下方式阻止NS3/NS5相互作用的化合物 虚拟放映。到目前为止，已经确定了一系列新的化合物 作为很有前途的蛋白水解酶抑制剂。化合物将通过迭代进一步优化 药物和组合化学，分子模拟，以获得有效和 选择性类药物铅分子。在《目标2》中，一种新的有效的抗病毒药物：我们 针对NS5 RdRP的7DA6MEPN已被发现可抑制DENV 复制。7-去氮-6-甲基嘌呤核糖核苷的其他类似物将是 综合评价，进一步提高本病的疗效和治疗指标 很有前途的抗病毒药物。在目标3中，根据目标1确定和合成的化合物 和2将通过体外酶试验(IC50)进一步评价其抑制效力 值)、细胞毒性分析(CC50值)、基于报告复制子的以及病毒 哺乳动物细胞培养中的感染性测定(EC50)。精选化合物显示 在NM范围内的抑制作用将通过ADME/TOX分析进行分析。

项目成果

Inhibition of Dengue virus and West Nile virus proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives.

• DOI: 10.1016/j.bmc.2011.12.047
• 发表时间: 2012-02-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Tiew, Kok-Chuan;Dou, Dengfeng;Teramoto, Tadahisa;Lai, Huiguo;Alliston, Kevin R.;Lushington, Gerald H.;Padmanabhan, R.;Groutas, William C.
• 通讯作者: Groutas, William C.

Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases.

• DOI: 10.1016/j.bmc.2012.10.058
• 发表时间: 2013-01-01
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Lai H;Dou D;Aravapalli S;Teramoto T;Lushington GH;Mwania TM;Alliston KR;Eichhorn DM;Padmanabhan R;Groutas WC
• 通讯作者: Groutas WC

Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold.

• DOI: 10.1016/j.bmc.2012.04.055
• 发表时间: 2012-07-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Aravapalli, Sridhar;Lai, Huiguo;Teramoto, Tadahisa;Alliston, Kevin R.;Lushington, Gerald H.;Ferguson, Eron L.;Padmanabhan, R.;Groutas, William C.
• 通讯作者: Groutas, William C.

Construction of dengue virus protease expression plasmid and in vitro protease assay for screening antiviral inhibitors.

登革热病毒蛋白酶表达质粒的构建和体外蛋白酶试验筛选抗病毒抑制剂。

• DOI: 10.1007/978-1-4939-0348-1_21
• 发表时间: 2014
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Lai,Huiguo;Teramoto,Tadahisa;Padmanabhan,Radhakrishnan
• 通讯作者: Padmanabhan,Radhakrishnan