Developing Broad-Spectrum Antivirals Targeting Coronavirus Replicase and Helicase

开发针对冠状病毒复制酶和解旋酶的广谱抗病毒药物

基本信息

批准号：
10513685
负责人：
Timothy Patrick Sheahan
金额：
$ 673.47万
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/10513685
关键词：
2019-nCoV 3-Dimensional Active Sites Acute Affect Affinity Air Allosteric Site Alveolar Antiviral Agents Antiviral Therapy Antiviral resistance Authorization documentation Automobile Driving Binding Biochemical Biochemistry Biological Biological Assay Biological Availability COVID-19 Cell Culture Techniques Cell model Cells Cessation of life Chemicals Chiroptera Chronic Collaborations Coronavirus Coronavirus Infections Coupled DNA Data Development Disease Disease model Drug Kinetics Drug Screening Drug Targeting Drug resistance Emergency Situation Enzymatic Biochemistry Enzymes Epidemic Etiology Evaluation Evolution FDA approved Formulation Future Generations Genetic Goals Government Hand Human In Vitro Industrialization Intravenous Lead Libraries Liquid substance Long COVID Lung Middle East Respiratory Syndrome Coronavirus Modeling Mutagenesis Nucleosides Oral Outpatients Pathogenesis Performance Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase III Clinical Trials Phenotype Positioning Attribute Process Productivity Property Public Health RNA Helicase RNA-Directed RNA Polymerase Research Personnel Resistance SARS coronavirus SARS-CoV-2 antiviral Safety Site Specificity Structural Models Structure-Activity Relationship System Therapeutic Treatment Efficacy Vaccinated Vaccination Validation Viral Viral Drug Resistance Virus Replication aged antiviral drug development base chemical group cost drug candidate drug development drug discovery efficacy study enzootic fitness health economics helicase human coronavirus improved in vitro Assay in vivo in vivo evaluation industry partner lead optimization molnupiravir novel novel coronavirus nucleoside analog pandemic disease pre-clinical preclinical efficacy preclinical evaluation preclinical study programs remdesivir replicase resistance mechanism resistance mutation reverse genetics screening small molecule small molecule libraries social synergism unvaccinated variants of concern virtual

项目摘要

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19 has caused over 700,000 deaths in the U.S. and over 4.8 million deaths worldwide. The pandemic’s true public health, economic and social cost continues to expand. Inadequate vaccination rates coupled with the perpetual evolution of SARS-CoV-2 variants of concern (VOCs) have fueled waves COVID-19 in unvaccinated and vaccinated groups. We led IND-enabling preclinical studies for two COVID-19 antiviral therapies: the FDA approved intravenous drug remdesivir and the oral antiviral, molnupiravir, which is now in Phase 3 clinical trial. For COVID- 19 and future emerging CoV epidemics, we need multiple oral broadly-active antivirals with disparate mechanisms of action to robustly inhibit virus replication and minimize the potential for resistance in outpatients. Here, in Project 2 of the READDI-AC program, we leverage decades of drug discovery, medicinal chemistry, biochemistry, enzymology and coronavirology expertise for the identification, validation, optimization and preclinical evaluation of novel small molecule antivirals targeting the conserved CoV RNA-dependent RNA polymerase (RdRp, nsp12) and helicase (Hel, nsp13). Together with the READDI-AC Core Labs and pharmaceutical leaders Takeda and Chimerix we articulate a platform for drug discovery and development in the following Specific Aims: 1) Identify and validate small molecules targeting SARS-CoV-2 RdRp and Helicase active and allosteric sites using multiple complementary approaches for discovery (e.g. fragment based, DNA- encoded library, small molecule enzymatic assay, and cell-based antiviral screens). As RdRp is a validated drug target, early discovery efforts prioritize Hel. Validated biochemical assays and cell-based antiviral assays drive hit discovery and iterative structure activity relationship (SAR) studies to improve upon and understand activity. We use “Fleximer” medicinal chemistry to generate new chemical matter from existing nucleoside analogs (e.g. Molnupiravir) and/or optimize hits from screening efforts. Top candidates will be evaluated and down selected based on antiviral performance in primary culture systems. 2) Medicinal chemistry transforms hits into leads in iterative SAR studies. For each lead, the breadth of antiviral activity, mechanism of action and resistance are determined in both biochemical and virologic assays. 3) We collaborate with industry partners to optimize leads into drug candidates for pharmacokinetic, safety and preclinical efficacy studies in robust models of acute and chronic COVID-19 disease. We have five leads currently in hand from Takeda, Chimerix, Pardes and academic collaborators for in vivo testing. Project 2 will provide a comprehensive IND-enabling preclinical data package for successful RdRp and Hel molecules positioning them for human trials.

抽象的严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 是 COVID-19 的病原体，已引起美国有超过 70 万人死亡，全球有超过 480 万人死亡。疫苗接种率不足以及不断的演变导致经济和社会成本不断扩大。值得关注的 SARS-CoV-2 (VOC) 已在未接种疫苗和恶性变种中引发了新冠肺炎 (COVID-19) 浪潮我们领导了两种 COVID-19 抗病毒疗法的 IND 临床前研究： FDA 批准了。静脉注射药物瑞德西韦和口服抗病毒药物 molnupiravir 目前正处于针对新冠病毒的 3 期临床试验中。 19 以及未来新出现的冠状病毒流行病，我们需要多种具有不同功效的口服广泛活性抗病毒药物强有力地抑制病毒复制并最大限度地减少门诊患者耐药可能性的作用机制。在 READDI-AC 计划的项目 2 中，我们利用了数十年的药物发现、药物化学、生物化学、酶学和冠状病毒学专业知识，用于识别、验证、优化和针对保守的 CoV RNA 依赖性 RNA 的新型小分子抗病毒药物的临床前评估聚合酶（RdRp、nsp12）和解旋酶（Hel、nsp13）以及 READDI-AC 核心实验室和制药领导者武田 (Takeda) 和 Chimerix 我们阐明了一个药物发现和开发平台具体目标如下： 1) 识别并验证针对 SARS-CoV-2 RdRp 和解旋酶的小分子使用多种互补方法来发现活性和变构位点（例如基于片段的、DNA- 编码库、小分子酶测定和基于细胞的抗病毒筛选）。目标、早期发现工作优先考虑经过验证的生化检测和基于细胞的抗病毒检测。命中发现和迭代结构活动关系 (SAR) 研究，以改进和理解活动。我们使用“Fleximer”药物化学从现有的核苷类似物（例如核苷类似物）中产生新的化学物质。 Molnupiravir）和/或筛选工作中的优化命中将被评估并被淘汰。 2) 药物化学将热门药物转化为先导药物对于每种先导药物，其抗病毒活性、作用机制和耐药性的广度都是迭代的 SAR 研究。 3) 我们与行业合作伙伴合作优化先导化合物。进入候选药物中，在急性和慢性疾病的稳健模型中进行药代动力学、安全性和临床前疗效研究我们目前掌握了武田 (Takeda)、Chimerix、Pardes 和学术界的 5 条线索。体内测试的合作者将提供全面的 IND 临床前数据包。成功将 RdRp 和 Hel 分子用于人体试验。