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.

项目总结 自2013年中东呼吸综合征冠状病毒(MERS-CoV)意外出现以来， 中东MERS的持续暴发以及MERS在全球传播的潜力就是例证 2015年韩国暴发疫情，突显了有效预防和预防的迫切需要 针对这种高毒力冠状病毒的治疗措施。MERS冠状病毒表达两种多蛋白 经过两种病毒编码的蛋白水解酶，一个是类似3C的蛋白水解酶(3CLpro)，另一个是类木瓜蛋白酶 蛋白水解酶，产生具有功能活性的蛋白质。MERS-CoV 3CLPro处理大部分切割 它位于多蛋白上，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 包括MERS冠状病毒和感染性腹膜炎在内的冠状病毒3CLPro的有效二肽抑制剂 冠状病毒(FIPV)是一种高毒力的猫科冠状病毒。使用FIPV作为模型，它是 实验证明，FIPV的先导化合物逆转了致命的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性的- MERS冠状病毒共有的特征，假设病毒蛋白水解酶抑制剂可以逆转 MERS冠状病毒在感染宿主中的致病机制。使用结构指导的方法，抗FIPV化合物 的结构进行了修饰，从而鉴定了哌啶衍生的先导化合物，这些化合物被发现 对MERS冠状病毒高度有效。因此，此R01应用程序的主要目标是标识 通过进行一系列基础和应用研究，体内验证了MERS-CoV临床前候选药物。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. 进行体外药效、生化、机理、结构、光谱和计算研究 确定类比的优先顺序，阐明作用机制，并加速优化过程。具体目标3. 评估优化的引线的物理化学性质、ADMET、PK和口服生物利用度。特定目标 4.在MERS-CoV感染小鼠模型中检测优化的LEAD的体内疗效。终极长篇 该计划的学期目标是通过推出一种候选药物来开发治疗MERS的抗病毒疗法 通过申请研究新药(IND)的阶段。