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属于贝塔冠状病毒属，编码两个大的重叠多聚蛋白 前体(pp1a和pp1ab)，四种结构蛋白(棘突、包膜、膜和 核衣壳)，以及几种辅助蛋白。这两种多蛋白(pp1a/pp1ab)必须被切割。 转化为它们各自的非结构蛋白，以成功复制病毒(1)。两种病毒蛋白水解酶 必需的和负责处理多蛋白的：类3C蛋白酶(3CL蛋白酶；CLPro 又称“主要蛋白酶”(MPRO)和类木瓜蛋白酶(PLPRO)(2)。重要的是，CLPRO 在底物的P1位的谷氨酰胺残基之后裂解多肽，这是唯一的 在其他人类蛋白酶中没有观察到的活性，表明这种病毒蛋白水解酶可以 被小分子抑制剂(3)特异性和选择性地抑制。PLPro也抑制先天的 从病毒和宿主蛋白中去除干扰素刺激基因15(ISG)的免疫反应。 因此，CLPRO和PLPRO都是口腔抗病毒开发的重要直接作用靶点。我们 将为这些目标中的每一个开发候选药物，从早期发现到后期领先优化。 在第一个目标中，我们有一个非共价的CLPro，我们在HIT中领导化学，并有 产生了一种适合PK研究的化合物，以潜在地测试体内疗效。在 第二个目标是我们正在启动对基于丙型肝炎病毒药物的PLPro Hit化合物的正式Hit评估 其他化学模板的目标是在第一年年底进入正式打击领先化学给予 对这一目标下药领域的总体挑战。此外，我们计划放映小说 PLPro和CLPro在斯克里普斯使用新的化学文库，通过核磁共振筛选和细胞为基础 记者分析说。该项目试图在晚期临床前阶段之间实现平衡 候选药物和针对这两个基本病毒药物靶点的新方法。