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Broad-spectrum therapeutics against SARS-CoV-2 3CL protease

针对 SARS-CoV-2 3CL 蛋白酶的广谱疗法

基本信息

批准号：
10471857
负责人：
ELIZABETH ANN FITZPATRICK
金额：
$ 65.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471857
关键词：
2019-nCoV Acids Affinity Animal Model Animals Anosmia Anti-Inflammatory Agents Antiviral Agents Antiviral Therapy Binding Biological Assay Biological Availability COVID-19 COVID-19 prevention COVID-19 therapeutics COVID-19 treatment Cell Culture Techniques Cells Characteristics China Coronavirus Coronavirus Infections Coughing Crystallization Cytochrome P450 Data Dexamethasone Diarrhea Disease Docking Drug Design Drug Kinetics Drug resistance Early treatment Enterovirus Enzyme Inhibition Enzymes Excretory function Exhibits Fever Glycoproteins Goals Healthcare Systems Hybrids In Vitro Infection Investigational New Drug Application Lead Libraries Ligands Liver Microsomes Lung Mesocricetus auratus Metabolism Modeling Molecular Norovirus Oral Outcome Pathogenicity Peptide Hydrolases Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Pneumonia Polyproteins Prevention Preventive Prophylactic treatment Protease Inhibitor Province Recombinant Proteins Resistance Ritonavir Roentgen Rays SARS-CoV-2 antiviral SARS-CoV-2 inhibitor Serum Shortness of Breath Speed Structure Structure-Activity Relationship System Testing Therapeutic Therapeutic Index Toxic effect Treatment Efficacy Vaccines Viral Viral Proteins Viremia Virus Virus Inhibitors Virus Replication Work absorption analog antiviral drug development aqueous base clinical development common symptom cytotoxicity design drug candidate drug discovery efficacy testing human coronavirus inhibitor lead optimization molecular modeling nanomolar nonhuman primate nucleoside analog pandemic coronavirus pandemic disease peptidomimetics pharmacophore preclinical study programs prophylactic protease E remdesivir screening sepsis induced ARDS small molecule small molecule inhibitor targeted agent virtual virtual screening

项目摘要

PROJECT SUMMARY/ABSTRACT COVID-19 was first identified in December 2019 in Wuhan, Hubei province, China, resulting in the ongoing 2019- 2020 pandemic. COVID-19 is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV- 2). Common symptoms of the disease include fever, dry cough, shortness of breath, diarrhea, and loss of smell. Complications may include pneumonia, viral sepsis, and acute respiratory distress syndrome. As of today, other than remdesivir, there is no approved small molecule drug for the treatment of COVID-19 and the discovery of an effective vaccine remains uncertain. Our long-term goal is to develop antiviral drugs for the treatment of COVID-19 and human coronavirus infections in general. Our central hypothesis is that inhibition of SARS-CoV- 2 polyprotein cleavage results in the prevention and early treatment of COVID-19 before it progresses to its more severe form. We will identify nanomolar inhibitors of the CoV 3C-like protease (3CLpro) suitable to be developed as antiviral agents for the treatment of COVID-19 and other coronavirus infections. The proposal targets the 3CLpro, a key enzyme for SARS-CoV-2 polyprotein cleavage and viral replication. Our overall premise is that small molecule inhibitors targeting this essential viral enzyme will inhibit replication, and therefore have the potential to be of both preventive and therapeutic value. Thus, our primary objective is to design and develop structure-based small-molecule inhibitors targeting coronavirus 3CLpro using our established and proven drug discovery expertise. Guided by strong preliminary data, the inhibition of polyprotein cleavage hypothesis will be tested by pursuing three specific aims: Aim 1) To inhibit SARS-CoV-2 polyprotein cleavage by developing covalent peptidic inhibitors of 3CLpro (nsp5).; Aim 2) To inhibit SARS-CoV-2 polyprotein cleavage by developing noncovalent nonpeptidic inhibitors of 3CLpro (nsp5).; and Aim 3) To determine the efficacy of covalent and noncovalent SARS-CoV-2 3CLpro inhibitors in a golden hamster model. Under the first aim, lead compound 3150 and its analogs will be tested in viral and enzyme assays for inhibitory activity of SARS-CoV-2 3CLpro. An aqueous soluble form of 3150 will be evaluated in the animal model. Structure-based drug design approaches will be employed to optimize 3150 for binding to the crystal structure of SARS-CoV-2 3CLpro. Under aim 2, Structure-based virtual screening and hybrid ligand screening approaches along with medicinal chemistry will be used to prepare and evaluate noncovalent nonpeptidic inhibitors of 3CLpro. Under the third aim, top-ranked SARS-CoV-2 3CLpro covalent and noncovalent inhibitors will be tested for pharmacokinetics and efficacy in a golden hamster COVID-19 model. The ultimate goal of the proposed studies is to advance an anti-COVID-19 drug candidate to the stage of filing an investigational new drug (IND) application. Overall, the results of this project will have a significant positive impact because they lay the groundwork for the clinical development of COVID-19 antiviral therapy and the potential to combine a potent and selective protease inhibitor with a nucleoside analog (e.g., remdesivir) and if needed anti-inflammatory drugs (e.g., dexamethasone or baricitinib).

项目概要/摘要 COVID-19 于 2019 年 12 月在中国湖北省武汉市首次发现，导致 2019- 2020年大流行。 COVID-19 是由严重急性呼吸系统综合症冠状病毒 2（SARS-CoV- 2）。该疾病的常见症状包括发烧、干咳、呼吸短促、腹泻和嗅觉丧失。并发症可能包括肺炎、病毒性败血症和急性呼吸窘迫综合征。截至今日，其他与瑞德西韦相比，目前还没有批准用于治疗 COVID-19 的小分子药物，并且发现有效的疫苗仍不确定。我们的长期目标是开发抗病毒药物来治疗一般而言，COVID-19 和人类冠状病毒感染。我们的中心假设是抑制 SARS-CoV- 2 多蛋白裂解可在 COVID-19 进一步发展之前对其进行预防和早期治疗严重的形式。我们将确定适合开发的 CoV 3C 样蛋白酶 (3CLpro) 的纳摩尔抑制剂作为治疗 COVID-19 和其他冠状病毒感染的抗病毒药物。该提案的目标是 3CLpro，SARS-CoV-2 多蛋白裂解和病毒复制的关键酶。我们的总体前提是针对这种重要病毒酶的小分子抑制剂将抑制复制，因此具有可能具有预防和治疗价值。因此，我们的首要目标是设计和开发使用我们成熟且经过验证的药物针对冠状病毒 3CLpro 的基于结构的小分子抑制剂发现专业知识。在强有力的初步数据的指导下，多蛋白裂解假说的抑制将是通过追求三个具体目标进行测试：目标 1) 通过开发抑制 SARS-CoV-2 多蛋白裂解 3CLpro (nsp5) 的共价肽抑制剂。；目标 2) 通过开发抑制 SARS-CoV-2 多蛋白裂解 3CLpro (nsp5) 的非共价非肽抑制剂。；目标 3) 确定共价和金仓鼠模型中的非共价 SARS-CoV-2 3CLpro 抑制剂。在第一个目标下，先导化合物 3150 及其类似物将在病毒和酶测定中测试 SARS-CoV-2 3CLpro 的抑制活性。一个 3150的水溶性形式将在动物模型中进行评估。基于结构的药物设计方法将用于优化 3150 与 SARS-CoV-2 3CLpro 晶体结构的结合。在目标 2 下，基于结构的虚拟筛选和混合配体筛选方法以及药物化学将用于制备和评估 3CLpro 的非共价非肽抑制剂。在第三个目标下，排名第一将测试 SARS-CoV-2 3CLpro 共价和非共价抑制剂的药代动力学和功效金仓鼠 COVID-19 模型。拟议研究的最终目标是推进抗 COVID-19 候选药物进入提交研究性新药（IND）申请阶段。总的来说，本次的结果项目将产生重大的积极影响，因为它们为临床开发奠定了基础 COVID-19 抗病毒疗法以及将有效的选择性蛋白酶抑制剂与核苷类似物（例如瑞德西韦）以及必要时的抗炎药物（例如地塞米松或巴瑞替尼）。