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togaviruses是全球发病率和死亡率的主要原因，或者是 准备发起未来的致命流行。这些病毒表达自己的半胱氨酸蛋白酶，mpro和 NSP2Pro，在其生命周期的早期处理病毒蛋白。这些蛋白质具有不同的结构特征 从人类蛋白酶中，可以用无负荷的底物类似物抑制它们，使其可定位 通过口服生物利用药物。最近开始针对口服SARSCOV2 MPRO抑制剂的临床试验验证 这类目标。现在需要一组多种蛋白质抑制剂来应对未来的抗药性和 为其他冠状病毒提供治疗。此外，没有蛋白酶抑制剂进入了临床试验 togaviruses，包括人类病原体基孔肯尼亚和委内瑞拉马chephaitis病毒。 Lin，Bogyo和Einav Labs开发了创新的方法来创建和测试病毒蛋白酶 抑制剂，包括（i）可渗透细胞的新型化学结构，具体抑制病毒蛋白酶， （ii）基于荧光素酶的快速评估活细胞中蛋白酶抑制作用，以及（iii）独特的人类肺类器官 （ALO）研究药物对病毒复制和组织损伤的影响。这个团队已经产生了潜力， SARSCOV2 MPRO的选择性和口服可生物利用抑制剂，称为ML10​​4M和ML1006M。这些 用于SARSCOV2复制，高血浆和肝细胞稳定性的EC50 <1μM和10％的口服 小鼠的生物利用度，在治疗范围内口服剂量后达到血浆浓度。 该项目的主要目的是将我们的铅Sarscov2 MPRO抑制剂推向成立阶段 同时推广我们对其他优先病毒的方法。 AIM 1将优化治疗指数（TI）和 SARSCOV2 MPRO抑制剂的药代动力学（PK）谱，并定义其治疗潜力。这包括 （a）优化对SARSCOV2 MPRO抑制的电流导线，并与使用酶降低衍生物 项目4; （b）分别测试这些铅的抗病毒效率，并与 项目3、4和6； （c）在小鼠中测试ALOS和效率，药代动力学和毒性的测试效率； （d） 选择IND候选人。 AIM 2将把我们的方法推广到其他冠状病毒和关键的togaviruses，以及 研究我们的抑制剂的作用机制。这包括（a）优化MERSCOV的电流线索，（b）创建 CHIKV和VEEV NSP2PRO的新抑制剂，以及（C）研究蛋白酶抑制剂在病毒寿命内作用 周期以及电阻如何出现。所有目标都将利用转化加速的活动， Synerx中心的大流行援助和结构生物学核心。 如果成功的话，该项目将迅速开发出SARSCOV2和其他冠状病毒的新型抑制剂 准备进入临床试验，并且有可能成为一流的试验。它也将建立证据 针对病毒蛋白酶的新方法的概念，其他冠状病毒的开发人员抑制剂和togaviruses的抑制剂 它不存在治疗选择，并表征蛋白质抑制剂治疗后期疾病的能力。