Inhibitors of SARS-CoV-2 proteases

修改项目摘要/摘要部分 SARS-CoV-2属于β冠状病毒属，编码两个大的重叠多聚蛋白 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）和几种辅助蛋白。两种多聚蛋白（pp1a/pp1ab）必须被切割 转化为单个的非结构蛋白，以成功复制病毒（1）。两种病毒蛋白酶是 重要的并负责加工多蛋白：3C样蛋白酶（3CL蛋白酶; CLpro 也称为"主蛋白酶"，Mpro）和木瓜蛋白酶样蛋白酶（PLpro）（2）。重要的是，CLPro 在底物的P1位置的谷氨酰胺残基后切割多肽，这是一种独特的 在其他人蛋白酶中未观察到活性，并表明这种病毒蛋白酶可以 被小分子抑制剂特异性和选择性地抑制（3）。PLpro还抑制了先天的 通过从病毒和宿主蛋白中去除干扰素刺激基因15（ISG）来增强免疫应答。 因此，CLpro和PLpro都是口服抗病毒药物开发的重要直接作用靶标。我们 将为每个目标开发候选药物，从早期发现到后期优化。 在第一个目标中，我们有一个非共价的CLpro，我们在其中引领化学， 产生了用于PK研究的合适化合物，以潜在地测试体内功效测试。在 第二个目标是，我们正在对基于HCV药物的PLpro命中化合物进行正式的命中评估， 其他化学模板的目标是在今年年底1进入正式命中导致化学给定 给这个目标下药的整体挑战此外，我们计划对新的 PLpro和CLpro在Scripps使用NMR筛选和基于细胞的新化学库 报告基因测定。该项目试图在后期临床前和临床前研究之间建立一个平衡的投资组合。 候选药物和针对这两种基本病毒药物靶标的新方法。

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.