新型冠状病毒3CL蛋白酶高效非共价抑制剂的研发

Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.

作者信息

Hou Ningke, Shuai Lei, Zhang Lijing, Xie Xuping, Tang Kaiming, Zhu Yunkai, Yu Yin, Zhang Wenyi, Tan Qiaozhu, Zhong Gongxun, Wen Zhiyuan, Wang Chong, He Xijun, Huo Hong, Gao Haishan, Xu You, Xue Jing, Peng Chen, Zou Jing, Schindewolf Craig, Menachery Vineet, Su Wenji, Yuan Youlang, Shen Zuyuan, Zhang Rong, Yuan Shuofeng, Yu Hongtao, Shi Pei-Yong, Bu Zhigao, Huang Jing, Hu Qi

机构信息

Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University; Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No.678 Haping Road, Xiangfang District, Harbin 150069, China.

出版信息

ACS Cent Sci. 2023 Jan 25;9(2):217-227. doi: 10.1021/acscentsci.2c01359. eCollection 2023 Feb 22.

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

3C样蛋白酶（3CLpro）是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和其他冠状病毒复制所必需的酶，因此是冠状病毒药物研发的一个靶点。到目前为止，几乎所有报道的冠状病毒3CLpro抑制剂都是共价抑制剂。在此，我们报告了3CLpro特异性非共价抑制剂的研发情况。其中最有效的一种，即WU-04，能有效阻断人细胞中的SARS-CoV-2复制，其半数有效浓度（EC）值在10纳摩尔范围内。WU-04还高效抑制SARS-CoV和中东呼吸综合征冠状病毒（MERS-CoV）的3CLpro，表明它是冠状病毒3CLpro的泛抑制剂。当以相同剂量口服给药时，WU-04在K18人血管紧张素转换酶2（hACE2）小鼠中显示出与PF-07321332（奈玛特韦）相似的抗SARS-CoV-2活性。因此，WU-04是一种很有前景的冠状病毒治疗候选药物。