Inhibitors of SARS-CoV-2 proteases

SARS-CoV-2 蛋白酶抑制剂

• 批准号: 10514324
• 负责人: Arnab Kumar Chatterjee
• 金额: $ 440.11万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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/10514324
• 关键词: 2019-nCoV; Active Sites; Affinity; Antiviral Agents; Binding; Biological Assay; Caspase; Catalytic Domain; Cells; Chemicals; Chemistry; Complex; DNA-Directed RNA Polymerase; Data; Development; Drug Targeting; Genes; Glutamine; Goals; Hepatitis C virus; Human; Hydrophobicity; In Vitro; Individual; Innate Immune Response; Institutes; Integral Membrane Protein; Interferons; Lactams; Lead; Libraries; Medicine; Membrane; Modeling; Mus; Nitriles; Nonstructural Protein; Nucleocapsid; Oral; Organelles; Papain; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Polymerase; Polyproteins; Positioning Attribute; Protease Inhibitor; Proteins; Publishing; Reporter; Reporting; SARS-CoV-2 inhibitor; SARS-CoV-2 protease; Site; Structural Protein; Structure; Testing; Viral; Viral Physiology; Virus Inhibitors; Virus Replication; animal efficacy; antiviral drug development; base; betacoronavirus; covalent bond; drug candidate; drug clearance; efficacy testing; in vivo; in vivo evaluation; inhibitor; lead candidate; lead optimization; molecular dynamics; molnupiravir; mouse model; novel; novel strategies; pandemic preparedness; peptidomimetics; polypeptide; pre-clinical; screening; small molecule; small molecule inhibitor; small molecule libraries; synergism; viral RNA

Modified Project Summary/Abstract Section SARS-CoV-2, belonging to the genus betacoronavirus, encodes two large overlapping polyprotein precursors (pp1a and pp1ab), four structural proteins (spike, envelope, membrane, and nucleocapsid), and several accessory proteins. The two polyproteins (pp1a/pp1ab) must be cleaved into their individual, nonstructural proteins for successful viral replication (1). Two viral proteases are essential and responsible for processing the polyproteins: the 3C-like protease (3CL protease; CLpro also referred to as “main protease”, Mpro) and a papain-like protease (PLpro) (2). Importantly, CLpro cleaves polypeptides after a glutamine residue in the P1 position of the substrate, which is a unique activity not observed in other human proteases and suggests that this viral protease can be specifically and selectively inhibited by a small molecule inhibitor (3). PLpro also suppresses the innate immune response by removing interfernon-stimulated gene 15 (ISG) from viral and host proteins. Therefore, both CLpro and PLpro are important direct-acting targets for oral anti-viral development. We will develop drug candidates for each of these targets, from early discovery to late lead optimization. In the first aim, we have a non-covalent CLpro where we are in hit to lead chemistry and have generated a suitable compound for PK studies to potentially test for in vivo efficacy testing. In the second aim we are initiating formal hit assessment on PLpro hit compounds based on HCV drugs and other chemical templates with the goal in the end of year 1 to enter formal hit to lead chemistry given the overall challenge in the field of drugging this target. Additionally, we plan on screening for novel PLpro and CLpro using novel chemical libraries at Scripps using NMR screening and cell-based reporter assays. This project attempts to have a balanced portfolio between late-stage preclinical drug candidates and novel approaches to these two essential viral drug targets.

修改后的项目摘要/摘要部分 SARS-CoV-2属于β冠状病毒属，编码两个大的重叠多蛋白 前体（pp1a 和 pp1ab）、四种结构蛋白（刺突蛋白、包膜蛋白、膜蛋白和 核衣壳）和一些辅助蛋白（pp1a/pp1ab）必须被切割。 进入各自的非结构蛋白以实现病毒的成功复制 (1)。 负责加工多蛋白：3C 样蛋白酶（3CL 蛋白酶；CLpro 也称为“主要蛋白酶”Mpro）和木瓜蛋白酶样蛋白酶 (PLpro) (2)。 在底物 P1 位置的谷氨酰胺残基后切割多肽，这是一种独特的 在其他人类蛋白酶中未观察到的活性，表明这种病毒蛋白酶可以 PLpro 被小分子抑制剂特异性且选择性地抑制 (3) 也会抑制先天性。 通过从病毒和宿主蛋白中去除干扰素刺激基因 15 (ISG) 来产生免疫反应。 因此，CLpro和PLpro都是口服抗病毒药物开发的重要直接作用靶点。 将为每个目标开发候选药物，从早期发现到后期先导优化。 在第一个目标中，我们有一个非共价 CLpro，我们可以在其中领导化学并有 生成了一种适合 PK 研究的化合物，可用于体内功效测试。 第二个目标是，我们正在启动基于 HCV 药物和 PLpro 命中化合物的正式命中评估 其他化学模板，目标是在第一年年底进入正式的领先化学领域 此外，我们计划筛选新的药物。 PLpro 和 CLpro 在斯克里普斯使用新型化学库，采用 NMR 筛选和基于细胞的方法 该项目试图在后期临床前试验之间建立平衡的组合。 候选药物和这两种重要病毒药物靶点的新方法。