Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies.
Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies.
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DOI：
10.1021/acsptsci.2c00206
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发表时间：
2022-12
影响因子：
6
通讯作者：
Chamandi S. Dampalla;Harry Nhat Nguyen;A. Rathnayake;Yunjeong Kim;K. D. Perera;Trent K Madden;Hayden A. Thurman;Alexandra J Machen;M. Kashipathy;Lijun Liu;K. Battaile;S. Lovell;Kyeong-Ok Chang;W. Groutas
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作者：
Chamandi S. Dampalla;Harry Nhat Nguyen;A. Rathnayake;Yunjeong Kim;K. D. Perera;Trent K Madden;Hayden A. Thurman;Alexandra J Machen;M. Kashipathy;Lijun Liu;K. Battaile;S. Lovell;Kyeong-Ok Chang;W. Groutas
COVID-19的病原体SARS-CoV-2的出现及其对全球健康的全球影响，为开发可用于对抗该病毒的有效对策提供了动力，包括疫苗，单克隆抗体和直接作用的抗病毒药物（DAA）。尽管做出了这些努力，但目前缺乏DAA已经迫切需要创建具有不同作用机制的广泛作用剂的增强和多样化组合，其可以有效地消除病毒感染。SARS-CoV-2 3C样蛋白酶（3CLpro）是病毒复制所必需的酶，是发现SARS-CoV-2治疗药物的有效靶点。在这份报告中，我们描述了结构指导的利用环丙烷部分的设计高效抑制剂的SARS-CoV-2 3CLpro，SARS-CoV-1 3CLpro，MERS-CoV 3CLpro。高分辨率的共晶结构被用来确定与抑制剂的酶的活性位点的结合和解开的作用机制的结构决定因素。醛5c和11 c抑制SARS-CoV-2复制，EC 50值分别为12和11 nM。此外，相应的醛亚硫酸氢盐加合物5d和11 d是等效的，EC 50值分别为13和12 nM。化合物5c /11 c和5d /11 d的安全指数（SI）值在7692和9090之间。重要的是，醛5c /11 c和亚硫酸氢盐加合物5d /11 d有效抑制MERS-CoV 3CLpro，IC 50值分别为80和120 nM以及70和70 nM。同样，化合物5c /11 c和5d /11 d抑制SARS-CoV-1，IC 50值分别为960和350 nM以及790和240 nM。总之，这些研究表明，本文所述的抑制剂具有低细胞毒性和高效力，并且是作为针对高致病性冠状病毒的广谱直接作用抗病毒剂进一步开发的有希望的候选物。
The advent of SARS-CoV-2, the causative agent of COVID-19, and its worldwide impact on global health, have provided the impetus for the development of effective countermeasures that can be deployed against the virus, including vaccines, monoclonal antibodies, and direct-acting antivirals (DAAs). Despite these efforts, the current paucity of DAAs has created an urgent need for the creation of an enhanced and diversified portfolio of broadly acting agents with different mechanisms of action that can effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CLpro), an enzyme essential for viral replication, is a validated target for the discovery of SARS-CoV-2 therapeutics. In this report, we describe the structure-guided utilization of the cyclopropane moiety in the design of highly potent inhibitors of SARS-CoV-2 3CLpro, SARS-CoV-1 3CLpro, and MERS-CoV 3CLpro. High-resolution cocrystal structures were used to identify the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and unravel the mechanism of action. Aldehydes 5c and 11c inhibited SARS-CoV-2 replication with EC50 values of 12 and 11 nM, respectively. Furthermore, the corresponding aldehyde bisulfite adducts 5d and 11d were equipotent with EC50 values of 13 and 12 nM, respectively. The safety index (SI) values for compounds 5c / 11c and 5d / 11d ranged between 7692 and 9090. Importantly, aldehydes 5c / 11c and bisulfite adducts 5d / 11d potently inhibited MERS-CoV 3CLpro with IC50 values of 80 and 120 nM, and 70 and 70 nM, respectively. Likewise, compounds 5c / 11c and 5d / 11d inhibited SARS-CoV-1 with IC50 values of 960 and 350 nM and 790 and 240 nM, respectively. Taken together, these studies suggest that the inhibitors described herein have low cytotoxicity and high potency and are promising candidates for further development as broad-spectrum direct-acting antivirals against highly pathogenic coronaviruses.