Research Project 1: Coronavirus antiviral lead development and combination testing

研究项目1：冠状病毒抗病毒先导药物开发和组合测试

基本信息

批准号：
10513684
负责人：
Ralph S Baric
金额：
$ 508.76万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10513684
关键词：
2019-nCoV Academia Academic Medical Centers Achievement Active Sites Animal Testing Antiviral Agents Biochemical Biological Assay Biological Sciences Biology COVID-19 COVID-19 pandemic COVID-19 treatment Chemicals Chemistry Chiroptera Collaborations Combined Modality Therapy Coronavirus Coronavirus Infections Data Development Dose Drug Design Drug Kinetics Epidemic Epithelial Cells Etiology Evaluation Evolution Future Genetic Goals Health Hospitalization Human In Vitro Industry Intravenous Laboratories Lead Libraries Modeling Oral Papain Pathogenesis Pathway interactions Peptide Hydrolases Pharmaceutical Preparations Phase III Clinical Trials Prevention Property Protease Inhibitor RNA Helicase RNA-Directed RNA Polymerase Reporting Research Research Project Grants Resistance Resistance profile Route SARS-CoV-2 infection Serial Passage Structure Structure-Activity Relationship Testing Toxic effect Validation Viral Pathogenesis Virus Work Zoonoses airway epithelium antiviral drug development antiviral nucleoside analog base betacoronavirus coronavirus antiviral coronavirus disease coronavirus treatment design drug development efficacy testing enzootic experience experimental study helicase human model in vitro testing in vivo in vivo Model in vivo evaluation industry partner inhibitor insight lead candidate lead optimization metabolic profile molnupiravir mouse model mutant novel novel coronavirus novel virus nucleoside analog pandemic disease pharmacokinetics and pharmacodynamics pre-clinical preclinical development preclinical study prevent programs remdesivir replicase resistance mutation screening uptake viral fitness viral resistance virus genetics

项目摘要

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 has profoundly impacted global human health and shown that it is imperative to develop antivirals for prevention and treatment of CoVs that are targeted to key required CoV replication functions and are orally available. The highly- collaborative CoV research programs in the Denison lab at Vanderbilt University Medical Center (VUMC) and the Sheahan and Baric labs at UNC Chapel Hill have been world leaders for over 30 years on CoV replication, evolution, pathogenesis, and countermeasures. Our programs led IND-enabling preclinical studies for the nucleoside analog antivirals remdesivir (RDV) and molnupiravir (MPV). For the current proposed READDI-AC AVIDD program, Project 1 (VUMC-Denison PI) and Project 2 (UNC-Sheahan PI) will pursue parallel but highly integrated antiviral discovery and development projects focused on distinct replicase functions. Project 1 (this project) will focus on the two essential virus encoded proteases nsp3-papain like protease (nsp3-PLPro) and nsp5-3C-like protease or main protease (nsp5-3CLPro / Mpro), while Project 2 will target antiviral development for the nsp12-RNA-dependent RNA polymerase and nsp13-helicase. For Project 1, we have assembled a team with deep experience and achievement in state-of-the-art drug design and chemistry, drug development, coronavirus protease biology, and in vivo models of human CoV (HCoV) infection from academia, industry and multiple-program Cores. The overall goal of Project 1 is to discover and develop direct-acting, orally-available, potent and broad-spectrum antivirals targeting CoV proteases and design combinations that boost activity and prevent the emergence of resistance against SARS-CoV-2 and other emerging coronaviruses. Studies in Aim 1 will discover and validate hits and prioritize and optimize lead compounds. For nsp5-3CLPro, we will initiate studies with established lead compounds from Pardes Biosciences. For nsp3-PLPro we use validated hits and ongoing discovery from a fragment-structure-based screening approach. We will determine activity, breadth, and toxicity of compounds in high-throughput virological assays and optimize uptake and metabolic profile of leads. Aim 2 will use lead compounds to define the genetic basis for viral resistance, viral fitness of resistance mutants, and mechanism of action. We will test leads from Project 1 in combination with other protease inhibitors, nucleoside analogs (RDV, MPV), and leads from Project 2. In Aim 3, we will optimize the in vivo PK/PD of chemical leads, determine the efficacy of optimized leads against SARS-CoV-2 and other CoV in vivo, determine the effect of resistance on in vivo efficacy, and test the efficacy of combinations. We already have a panel of lead compounds and validated hits from partners against both nsp5-3CLPro and nsp3-PLpro that will enter the pipeline in Aims 2 and 3, as well as multiple early hit candidates for development. Thus, Project 1 will have compounds at all stages from fundamental discovery to advanced leads with oral availability, animal testing and IND enabling pharmacokinetic studies at the outset and through the course of the project.

抽象的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)，即 COVID-19 的病原体，已深刻影响了全球人类健康，表明必须开发抗病毒药物来预防和治疗针对冠状病毒复制功能所需的关键且可口服的冠状病毒治疗。高度- 范德比尔特大学医学中心 (VUMC) 丹尼森实验室的 CoV 合作研究项目北卡罗来纳大学教堂山分校的 Sheahan 和 Baric 实验室 30 多年来在冠状病毒复制方面一直处于世界领先地位，演变、发病机制和对策。我们的项目主导了支持 IND 的临床前研究核苷类似物抗病毒药物瑞德西韦 (RDV) 和莫努匹拉韦 (MPV)。对于当前提议的 READDI-AC AVIDD 计划、项目 1 (VUMC-Denison PI) 和项目 2 (UNC-Sheahan PI) 将追求并行但高度综合抗病毒发现和开发项目侧重于不同的复制酶功能。项目1（本项目）将重点关注两种重要的病毒编码蛋白酶 nsp3-木瓜蛋白酶样蛋白酶 (nsp3-PLPro) 和 nsp5-3C类蛋白酶或主要蛋白酶（nsp5-3CLPro / Mpro），而项目2将针对抗病毒开发用于 nsp12-RNA 依赖性 RNA 聚合酶和 nsp13-解旋酶。对于项目 1，我们组建了一个团队在最先进的药物设计和化学、药物开发方面拥有丰富的经验和成就，来自学术界、工业界和学术界的冠状病毒蛋白酶生物学以及人类冠状病毒 (HCoV) 感染的体内模型多程序核心。项目 1 的总体目标是发现和开发直接作用、口服、针对 CoV 蛋白酶的强效广谱抗病毒药物，并设计可增强活性和防止出现针对 SARS-CoV-2 和其他新出现的冠状病毒的耐药性。目标 1 的研究将发现并验证命中并优先考虑和优化先导化合物。对于nsp5-3CLPro，我们将启动使用 Pardes Biosciences 已确定的先导化合物进行研究。对于 nsp3-PLPro，我们使用经过验证的命中和基于片段结构的筛选方法的持续发现。我们将确定活动、广度和高通量病毒学检测中化合物的毒性，并优化先导化合物的摄取和代谢特征。目标 2 将使用先导化合物来定义病毒抗性的遗传基础、抗性突变体的病毒适应性、和作用机制。我们将测试项目 1 的先导化合物与其他蛋白酶抑制剂的组合，核苷类似物（RDV、MPV）以及项目 2 的先导化合物。在目标 3 中，我们将优化以下药物的体内 PK/PD：化学先导物，确定优化先导物在体内对抗 SARS-CoV-2 和其他 CoV 的功效，确定耐药性对体内功效的影响，并测试组合的功效。我们已经有一个小组先导化合物和合作伙伴针对 nsp5-3CLPro 和 nsp3-PLpro 的经过验证的命中将进入目标 2 和 3 中的管道，以及多个早期热门候选药物的开发。因此，项目 1 将有化合物处于从基础发现到口服可用性、动物测试和高级先导化合物的各个阶段 IND 在项目一开始和整个项目过程中都能够进行药代动力学研究。