Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).
Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV).
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DOI：
10.1016/j.ejmech.2023.115376
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发表时间：
2023-06-05
影响因子：
6.7
通讯作者：
Groutas, William C.
中科院分区：
文献类型：
--
作者：
Dampalla, Chamandi S.;Miller, Matthew J.;Kim, Yunjeong;Zabiegala, Alexandria;Nguyen, Harry Nhat;Madden, Trent K.;Thurman, Hayden A.;Machen, Alexandra J.;Cooper, Anne;Liu, Lijun;Battaile, Kevin P.;Lovell, Scott;Chang, Kyeong-Ok;Groutas, William C.
关键词：
COVID-19的病原SARS-CoV-2感染相关的高发病率和死亡率对全球公共卫生产生了重大影响。在一系列疫苗和生物制剂的开发方面取得了重大进展，然而，SARS-CoV-2变体和突破性感染的出现仍然是一个主要问题。此外，目前缺乏可用于对抗SARS-CoV-2以及任何新出现和再出现的冠状病毒传播的小分子宿主和病毒导向治疗和预防药物。我们在此描述了我们的努力，通过专注于SARS-CoV-2 3c样蛋白酶（3CLpro或主蛋白酶）的有效广谱抑制剂的结构指导设计来解决这一迫切需求，该酶是病毒复制所必需的酶。抑制剂利用与gem-二甲基存在相关的定向效应，使抑制剂与酶的S4亚位点最佳地相互作用。在生化和细胞实验中发现几种化合物能有效抑制SARS-CoV-2和MERS-CoV 3CL蛋白酶。其中，醛1c及其亚硫酸酯加合物1d对SARS-CoV-2的EC50值分别为12 nM和10 nM， CC50值为50 μM。此外，这些化合物的氘化反应得到的化合物2c/2d的EC50值分别为11和12 nM。用腈（CN）或α-酮酰胺战斗部或其相应的亚硫酸酯加合物取代乙醛战斗部，分别得到EC50值为60、50和70 nM的化合物1g、1e和1f。高分辨率的共晶结构已经确定了与抑制剂与酶活性位点结合相关的结构决定因素，并且进一步阐明了抑制剂的作用机制。总的来说，这些化合物显示出的高安全指数（SI） （SI=CC50/EC50）表明它们非常适合进行进一步的临床前研究。
The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. We describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CLpro or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were >50 μM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an α-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1eand1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
7.3
作者：
Gao, Shenghua;Song, Letian;Liu, Xinyong
通讯作者：
Liu, Xinyong
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
56.9
作者：
Dai, Wenhao;Zhang, Bing;Liu, Hong
通讯作者：
Liu, Hong