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.

修改的项目摘要/摘要部分 SARS-COV-2（属于Betacoronavirus属）编码两个大重叠多蛋白 前体（PP1A和PP1AB），四个结构蛋白（尖峰，信封，膜和 Nucleocapsid）和几种辅助蛋白。必须将两个多蛋白（PP1A/PP1AB）切割 进入其个体的非结构蛋白，以成功地复制病毒（1）。两个病毒蛋白是 必不可少的，负责处理多蛋白：3C样蛋白酶（3Cl蛋白酶； clpro） 也称为“主蛋白”，mpro）和木瓜蛋白酶样蛋白（PLPRO）（2）。重要的是，clpro 在底物的P1位置的谷氨酰胺居住后切割多肽，这是独特的 在其他人蛋白酶中未观察到的活性，并表明该病毒蛋白酶可以是 PLPRO也抑制了先天 免疫反应通过从病毒和宿主蛋白中去除干扰素刺激的基因15（ISG）。 因此，CLPRO和PLPRO都是口服抗病毒发育的重要直接作用靶标。我们 从早期发现到晚期铅优化，将为每个目标开发候选药物。 在第一个目的中，我们有一个非共价clpro，我们在铅化学中受到打击，并具有 生成了适合PK研究的合适化合物，以潜在地测试体内效率测试。在 第二个目的，我们将对基于HCV药物的PLPRO HIT化合物进行正式评估和 其他化学模板的目标是在第1年年底进入正式命中率进行铅化学的目标 吸毒该目标领域的总体挑战。此外，我们计划筛选新颖 PLPRO和CLPRO使用NMR筛选和基于细胞的新型化学文库在Scripps上使用新型化学文库 记者测定法。该项目试图在晚期临床前之间具有平衡的投资组合 候选药物和新方法的新方法。