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

• 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
• 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

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 严重的急性呼吸道综合征冠状病毒2（SARS-COV-2），COVID-19的病因学药 对全球人类健康产生了深远的影响，并表明必须开发预防和 针对关键所需COV复制功能的关键的COV处理并且可以口服。高度 - 范德比尔特大学医学中心（VUMC）和 UNC Chapel Hill的Sheahan和Baric Labs在COV复制方面一直是世界领导人， 进化，发病机理和对策。我们的计划领导了针对临床前研究的 核苷类模拟抗病毒药remdesivir（RDV）和molnupiravir（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）将并行但高度 集成的抗病毒发现和开发项目集中在不同的复制酶功能上。项目1（这 项目）将重点介绍两个必需病毒编码的蛋白酶NSP3-蛋白酶（如蛋白酶）（NSP3-PLPRO）和 NSP5-3C样蛋白酶或主蛋白酶（NSP5-3CLPRO / MPRO），而项目2将靶向抗病毒发育 对于NSP12-RNA依赖性RNA聚合酶和NSP13-螺旋酶。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，药物开发方面具有丰富的经验和成就， 冠状病毒蛋白酶生物学以及学术界，工业和工业和人类COV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，口服可用， 靶向COV蛋白酶和设计组合的有效和广谱抗病毒药，可提高活性和 防止对SARS-COV-2和其他新兴冠状病毒的抵抗力。 AIM 1的研究1 将发现并验证命中，并确定并优化铅化合物。对于NSP5-3Clpro，我们将启动 研究了来自Pardes Biosciences的已建立铅化合物的研究。对于NSP3-PLPRO，我们使用经过验证的命中和 从基于碎片结构的筛选方法中进行的持续发现。我们将确定活动，广度和 高通量病毒学测定中化合物的毒性，并优化铅的摄取和代谢概况。 AIM 2将使用铅化合物来定义病毒抗性，抗性突变体病毒适应性的遗传基础， 和作用机理。我们将与其他蛋白酶抑制剂联合测试项目1的潜在客户， 核苷类似物（RDV，MPV），以及项目2的引线。在AIM 3中，我们将优化体内PK/PD 化学铅，确定针对SARS-COV-2和其他COV在体内优化铅的功效，确定 抗性对体内功效的影响，并测试组合功效。我们已经有一个面板 铅化合物和合作伙伴对NSP5-3CLPRO和NSP3-PLPRO的验证，将输入 AIMS 2和3中的管道以及多个早期命中的候选人进行开发。因此，项目1将有 从基本发现到高级潜在客户的各个阶段的化合物，口服可用性，动物测试和 一开始就可以在项目过程中实现药代动力学研究。