Yang Qi, Huang Xupeng, Zhang Hongbo, Sun Jing, Tang Jielin, Chen Zhao, Liu Lijie, Liu Man, Sun Zeyun, Tang Zhenhao, Wei Dandan, Wang Dong, Wang Yiliang, Yan Mengrong, Zhao Li, Zhu Airu, Zhong Yihang, Yang Haitao, Zhao Yao, Dai Jun, Shi Yongxia, Huang Bo, Zhang Wei, Zhao Jincun, Chen Xinwen, Rao Zihe, Peng Wei
State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China; Guangzhou National Laboratory, Guangzhou, 510005, China.
Guangzhou National Laboratory, Guangzhou, 510005, China; Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China.
Eur J Med Chem. 2025 May 5;289:117497. doi: 10.1016/j.ejmech.2025.117497. Epub 2025 Mar 10.
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and continues to pose serious threats to global public health. The main protease (M) of SARS-CoV-2 is crucial for viral replication and its conservation, making it an attractive drug target. Here, we employed a structure-based drug design strategy to develop and optimize novel inhibitors targeting SARS-CoV-2 M. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC) values below 20 nM. The cocrystal structure of M with compound 10 highlighted the crucial roles of the interactions within the S3/S4 pockets in inhibitor potency enhancement. These findings demonstrated that expanding the utilization of these binding pockets was an effective strategy for developing noncovalent small molecule inhibitors that target SARS-CoV-2 M. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC of 9.4 nM. Moreover, oral treatment with compounds 1 and 9 exhibited excellent antiviral potency and substantially ameliorated virus-induced tissue damage in the lungs of Omicron BA.5-infected K18-human ACE2 (K18-hACE2) transgenic mice, indicating that these novel noncovalent inhibitors could be potential oral agents for the treatment of COVID-19.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的2019冠状病毒病（COVID-19）大流行已导致数百万人死亡，并继续对全球公共卫生构成严重威胁。SARS-CoV-2的主要蛋白酶（M）对病毒复制及其保存至关重要，使其成为一个有吸引力的药物靶点。在此，我们采用基于结构的药物设计策略来开发和优化针对SARS-CoV-2 M的新型抑制剂。通过充分探索S1、S2和S3/S4结合口袋的占据情况，我们鉴定出了8种有前景的抑制剂，其半数最大抑制浓度（IC）值低于20 nM。M与化合物10的共晶体结构突出了S3/S4口袋内相互作用在增强抑制剂效力方面的关键作用。这些发现表明，扩大这些结合口袋的利用是开发靶向SARS-CoV-2 M的非共价小分子抑制剂的有效策略。化合物4对野生型SARS-CoV-2表现出出色的体外抗病毒活性，其半数有效浓度（EC）为9.4 nM。此外，用化合物1和9进行口服治疗在感染奥密克戎BA.5的K18-人血管紧张素转换酶2（K18-hACE2）转基因小鼠的肺部表现出出色的抗病毒效力，并显著改善了病毒诱导的组织损伤，表明这些新型非共价抑制剂可能是治疗COVID-19的潜在口服药物。
