Development of selective and potent protease inhibitors for corona and other pandemic viruses

开发针对冠状病毒和其他大流行病毒的选择性有效蛋白酶抑制剂

• 批准号: 10514273
• 负责人: Michael Z. Lin
• 金额: $ 289.73万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514273
• 关键词: 2019-nCoV; ADME Study; Acceleration; Active Sites; Adult; Antiviral Therapy; Biological Assay; Biological Availability; Caspase; Cells; Cellular Structures; Charge; Chemical Structure; Chemicals; Chikungunya virus; Chiroptera; Clinic; Clinical; Clinical Trials; Collaborations; Consult; Coronavirus; Crystallization; Cultured Cells; Cysteine; Data; Development; Disease; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Enzymes; Epidemic; Epoxy Compounds; Equus caballus; Exhibits; Future; Genetic; Goals; Hamsters; Hepatocyte; Human; In Vitro; Individual; Infection; Inflammation; Lead; Life Cycle Stages; Luciferases; Lung; Measures; Methods; Modeling; Morbidity - disease rate; Mus; Mutation; Names; Nonstructural Protein; Oral; Organoids; Outpatients; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Plasma; Polyproteins; Population; Process; Protac; Protease Inhibitor; Proteins; RNA Viruses; Regimen; Resistance; Structure; Testing; Therapeutic; Therapeutic Index; Togaviridae; Toxic effect; Toxicology; Venezuelan Equine Encephalitis Virus; Viral; Viral Load result; Viral Proteins; Virus; Virus Replication; Work; analog; anti-viral efficacy; antiviral drug development; base; chikungunya; coronavirus disease; design; drug candidate; drug discovery; efficacy testing; genotoxicity; human model; human pathogen; in vitro activity; in vivo; inhibitor; inhibitor therapy; innovation; mortality; mutant; novel; novel therapeutics; pandemic disease; peptidomimetics; resistance mechanism; reverse genetics; structural biology; tissue injury

ABSTRACT: Coronaviruses and togaviruses are major causes of morbidity and mortality worldwide, or are poised to initiate future deadly epidemics. These viruses express their own cysteine proteases, Mpro and nsP2pro, to process viral proteins early in their life cycles. These proteases have structural features distinct from human proteases, and they can be inhibited with uncharged substrate analogs, making them targetable by orally bioavailable drugs. The recent initiation of clinical trials for an oral SARSCoV2 Mpro inhibitor validates this class of targets. A diverse set of protease inhibitors are now needed to counter future resistance and provide treatments for other coronaviruses. Further, no protease inhibitors have entered clinical trials for togaviruses, including the human pathogens Chikungunya and Venezuelean Equine Encephaitis Viruses. The Lin, Bogyo, and Einav Labs have developed innovative approaches to create and test viral protease inhibitors, including (i) novel chemical structures that are cell permeable and specifically inhibit viral proteases, (ii) a rapid luciferase-based assay of protease inhibition in living cells, and (iii) unique human adult lung organoids (ALOs) to study the effects of drugs on virus replication and tissue injury. This team has already generated potent, selective, and orally bioavailable inhibitors of SARSCoV2 Mpro, named ML104m and ML1006m. These compounds exhibit EC50 < 1 μM for SARSCoV2 replication, high plasma and hepatocyte stability, and 10% oral bioavailability in mice, achieving plasma concentrations after oral dosing in the therapeutic range. The main goal of this project is to advance our lead SARSCoV2 Mpro inhibitors into the IND-enabling stage while generalizing our approach to other priority viruses. Aim 1 will optimize the therapeutic index (TI) and pharmacokinetic (PK) profile of SARSCoV2 Mpro inhibitors, and define their therapeutic potential. This includes (A) optimizing current leads for SARSCoV2 Mpro inhibition and generating enzyme-degrading derivatives with Project 4; (B) testing these leads for antiviral efficacy individually and in combination with compounds from Projects 3, 4, and 6; (C) testing efficacy in ALOs and efficacy, pharmacokinetics, and toxicity in mice; and (D) selecting IND candidates. Aim 2 will generalize our methods to other coronaviruses and key togaviruses, and study our inhibitors’ mechanisms of action. This includes (A) optimizing current leads for MERSCoV, (B) creating new inhibitors of CHIKV and VEEV nsP2pro, and (C) studying when protease inhibitors act within the viral life cycle and how resistance emerges. All Aims will leverage the activities of the Translational Acceleration, Pandemic Assistance, and Structural Biology cores of the SyneRx Center. If successful, this project will rapidly develop novel inhibitors for SARSCoV2 and other coronaviruses that are ready to enter clinical trials and that have the potential to be best-in-class. It will also establish proof of concept for new ways to target viral proteases, develop inhibitors for other coronaviruses and togaviruses for which no treatment options exist, and characterize the ability of protease inhibitors to treat late-stage disease.

摘要：冠状病毒和披膜病毒是全世界发病和死亡的主要原因，或者说是 这些病毒表达自己的半胱氨酸蛋白酶 Mpro 和 Mpro，准备引发未来的致命流行病。 nsP2pro，在病毒蛋白生命周期的早期处理这些蛋白酶具有独特的结构特征。 来自人类蛋白酶，并且可以用不带电荷的底物类似物抑制它们，从而使其成为靶向 最近启动的口服 SARSCoV2 Mpro 抑制剂的临床试验得到了验证。 现在需要一系列不同的蛋白酶抑制剂来应对未来的耐药性和 此外，还没有蛋白酶抑制剂进入临床试验。 披膜病毒，包括人类病原体基孔肯雅病毒和委内瑞拉马脑炎病毒。 Lin、Bogyo 和 Einav 实验室开发了创新方法来创建和测试病毒蛋白酶 抑制剂，包括（i）具有细胞渗透性并特异性抑制病毒蛋白酶的新颖化学结构， (ii) 基于荧光素酶的活细胞蛋白酶抑制快速检测，以及 (iii) 独特的成人肺类器官 （ALO）研究药物对病毒复制和组织损伤的影响该团队已经产生了有效的、 SARSCoV2 Mpro 的选择性口服生物利用抑制剂，命名为 ML104m 和 ML1006m。 化合物对 SARSCoV2 复制表现出 EC50 < 1 μM、高血浆和肝细胞稳定性以及 10% 口服 小鼠的生物利用度，口服给药后达到治疗范围内的血浆浓度。 该项目的主要目标是将我们的主要 SARSCoV2 Mpro 抑制剂推进到 IND 启动阶段 同时将我们的方法推广到其他优先病毒上，目标 1 将优化治疗指数 (TI) 和 SARSCoV2 Mpro 抑制剂的药代动力学 (PK) 概况，并确定其治疗潜力。 (A) 优化当前用于抑制 SARSCoV2 Mpro 的引线并生成酶降解衍生物 项目 4；(B) 单独测试这些先导化合物以及与来自以下化合物的组合的抗病毒功效 项目 3、4 和 6；(C) 测试 ALO 的功效以及小鼠体内的功效、药代动力学和毒性； 选择 IND 候选者将我们的方法推广到其他冠状病毒和关键披膜病毒，以及 研究我们的抑制剂的作用机制，这包括 (A) 优化 MERSCoV 的现有线索，(B) 创造。 CHIKV 和 VEEV nsP2pro 的新抑制剂，以及 (C) 研究蛋白酶抑制剂何时在病毒生命中发挥作用 周期以及阻力如何出现。所有目标将利用转化加速的活动， SyneRx 中心的流行病援助和结构生物学核心。 如果成功，该项目将迅速开发针对 SARSCoV2 和其他冠状病毒的新型抑制剂 已准备好进入临床试验，并且有潜力成为同类最佳产品，这也将建立证据。 针对病毒蛋白酶的新方法概念，开发其他冠状病毒和披膜病毒的抑制剂 不存在治疗选择，并表征了蛋白酶抑制剂治疗晚期疾病的能力。