Small Molecule Protease Inhibitors against MERS-CoV

针对中东呼吸综合征冠状病毒的小分子蛋白酶抑制剂

• 批准号: 10396522
• 负责人: Kyeong-Ok Chang
• 金额: $ 72.86万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396522
• 关键词: Adverse effects; Affect; Antiviral Agents; Binding Proteins; Biochemical; Biological Assay; Biological Availability; Bioterrorism; Category C pathogen; Cell Culture Techniques; Cells; Coronavirus; Coronavirus Infections; Development; Dipeptidyl Peptidases; Dipeptidyl-Peptidase IV; Disease Outbreaks; Disease Progression; Drug Design; Drug Kinetics; Elements; Enzymes; Feline Coronavirus; Feline infectious peritonitis virus; Felis catus; Goals; Health; Human; Immune; In Vitro; Investigational New Drug Application; Knock-in; Knock-in Mouse; Lead; Measures; Mediating; Metabolism; Middle East; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Oral; Papain; Pathogenesis; Peptide Hydrolases; Peritonitis; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Plasma; Plasma Proteins; Polyproteins; Prevention; Preventive; Process; Property; Protease Inhibitor; Proteins; Proteolytic Processing; Public Health; RNA Viruses; Reporting; Research; Respiratory Disease; SARS coronavirus; Series; Site; Solubility; South Korea; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Vaccines; Viral; Virulent; Virus; Virus Replication; X-Ray Crystallography; analog; anti-viral efficacy; antiviral drug development; base; betacoronavirus; chemical stability; computer studies; coronavirus receptor; cytotoxicity; design; drug candidate; in vivo; inhibitor; lead optimization; lead series; lipophilicity; mortality; mouse model; novel; piperidine; pre-clinical; process optimization; programs; public health emergency; resistance mechanism; small molecule; small molecule therapeutics; spectroscopic survey; therapeutic target; transmission process; viral resistance

PROJECT SUMMARY Since the unexpected emergence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2013, the ongoing outbreaks of MERS in the Middle East and the potential for global transmission of MERS, exemplified by an outbreak in South Korea in 2015, have underscored the urgent need for effective preventive and therapeutic measures against this highly virulent coronavirus. MERS-CoV expresses two polyproteins that undergo proteolytic processing by two virus-encoded proteases, a 3C-like protease (3CLpro) and a papain-like protease, to generate functionally active proteins. MERS-CoV 3CLpro processes the majority of the cleavage sites on the polyproteins and is essential for viral replication, making it an attractive therapeutic target. A series of potent dipeptidyl inhibitors of the 3CLpro of coronaviruses including MERS-CoV and infectious peritonitis coronavirus (FIPV), a highly virulent feline coronavirus, have been generated. Using FIPV as a model, it was demonstrated that the lead compound for FIPV reverses the progression of fatal FIP in experimentally or naturally infected cats. Since FIP disease progression is quite rapid and its pathogenesis primarily immune- mediated, features shared by MERS-CoV, it was hypothesized that a viral protease inhibitor could reverse the pathogenesis of MERS-CoV in affected hosts. Using a structure-guided approach, the anti-FIPV compound was structurally modified resulting in the identification of piperidine-derived lead compounds that were found to be highly effective against MERS-CoV. Thus, the primary goal of this R01 application is the identification of an in-vivo validated MERS-CoV preclinical candidate by conducting an array of basic and applied studies. Four aims are proposed to achieve this objective. Specific Aim 1. Optimize the piperidine-derived lead series of MERS-CoV 3CLpro inhibitors by iterative medicinal chemistry and structure-based drug design. Specific Aim 2. Conduct in vitro efficacy, biochemical, mechanistic, structural, spectroscopic, and computational studies to prioritize analogs, elucidate the mechanism of action, and accelerate the optimization process. Specific Aim 3. Evaluate the physicochemical properties, ADMET, PK, and oral bioavailability of optimized leads. Specific Aim 4. Determine in vivo efficacy of optimized leads in mouse models of MERS-CoV infection. The ultimate long term goal of this program is the development of antiviral therapeutics for MERS by advancing a drug candidate through the stage of filing for an investigational new drug (IND) application.

项目摘要 自2013年中东呼吸综合征冠状病毒（MERS-CoV）意外出现以来， 中东地区正在爆发的MERS疫情以及MERS全球传播的可能性， 2015年在韩国爆发，强调了有效预防和 针对这种高毒性冠状病毒的治疗措施。MERS-CoV表达两种多蛋白， 通过两种病毒编码的蛋白酶进行蛋白水解加工，3C样蛋白酶（3CLpro）和木瓜蛋白酶样蛋白酶（3CLpro）。 蛋白酶，以产生功能活性蛋白。MERS-CoV 3CLpro处理大部分切割 多聚蛋白上的位点，是病毒复制所必需的，使其成为有吸引力的治疗靶点。一系列 冠状病毒（包括MERS-CoV和感染性腹膜炎）3CLpro的有效二肽基抑制剂 已经产生了一种高毒性猫冠状病毒（FIPV）。使用FIPV作为模型， 证明FIPV的先导化合物在实验或临床试验中逆转了致死性FIP的进展， 自然感染的猫。由于FIP疾病进展相当迅速，其发病机制主要是免疫- 由于MERS-CoV具有共同的介导的特征，因此假设病毒蛋白酶抑制剂可以逆转MERS-CoV的表达， MERS-CoV在受影响宿主中的发病机制。使用结构指导的方法，抗FIPV化合物 结构上进行了修改，导致识别哌啶衍生的先导化合物，发现 对中东呼吸综合征病毒非常有效。因此，此R 01应用程序的主要目标是识别 通过进行一系列基础和应用研究，体内验证MERS-CoV临床前候选物。四 提出了实现这一目标的目标。具体目标1.优化哌啶衍生的铅系列 MERS-CoV 3CLpro抑制剂通过迭代药物化学和基于结构的药物设计。具体目标2。 进行体外功效、生化、机理、结构、光谱和计算研究， 确定类似物的优先顺序，阐明作用机制，并加速优化过程。具体目标3。 评价优化电极导线的理化性质、ADMET、PK和口服生物利用度。具体目标 4.在MERS-CoV感染的小鼠模型中确定优化的引线的体内功效。最长的 该计划的长期目标是通过开发候选药物来开发MERS的抗病毒治疗方法 通过提交研究性新药（IND）申请的阶段。