Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease.
Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease.
复制标题
DOI：
10.1021/acsinfecdis.3c00565
复制
发表时间：
2024-01
影响因子：
5.3
通讯作者：
M. Ashraf-Uz-Zaman;Teck Khiang Chua;Xin Li;Yuan Yao;Bala Krishna Moku;Chandra Bhushan Mishra;V. Avadhanula;P. Piedra;Yongcheng Song
中科院分区：
文献类型：
--
作者：
M. Ashraf-Uz-Zaman;Teck Khiang Chua;Xin Li;Yuan Yao;Bala Krishna Moku;Chandra Bhushan Mishra;V. Avadhanula;P. Piedra;Yongcheng Song
自2019年出现以来，高度传染性的SARS-CoV-2冠状病毒已感染全球数十亿人，并出现流感样症状。它已造成数百万人死亡。病毒主要蛋白酶（Mpro）是SARS-CoV-2复制所必需的，因此是药物靶点。设计并合成了几个系列的Mpro共价抑制剂。构效关系研究表明，（1）几种以Cys 145为靶点的氯乙酰胺和环氧化物为基础的化合物是有效的抑制剂，IC 50值低至0.49 μM;（2）Mpro的Cys 44不亲核，无法进行共价抑制剂设计。高分辨率X射线研究揭示了蛋白质-抑制剂相互作用和抑制机制。令人感兴趣的是，Cys 145优选攻击几种环氧化物抑制剂的受阻Cα原子。发现氯乙酰胺抑制剂13和环氧化物抑制剂30抑制细胞SARS-CoV-2复制，EC 68（病毒滴度的半对数减少）为3和5 μM。这些化合物代表了抗SARS-CoV-2药物开发的新药理学先导。
Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure-activity relationship studies show that (1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC50 values as low as 0.49 μM and (2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High-resolution X-ray studies revealed the protein-inhibitor interactions and mechanisms of inhibition. It is of interest that Cys145 preferably attacks the more hindered Cα atom of several epoxide inhibitors. Chloroacetamide inhibitor 13 and epoxide inhibitor 30 were found to inhibit cellular SARS-CoV-2 replication with an EC68 (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development.