Zhou Xuelan, Lu Xiaolu, Lin Cheng, Zou Xiaofang, Li Wenwen, Zeng Xiangyi, Wang Jie, Zeng Pei, Wang Weiwei, Zhang Jin, Jiang Haihai, Li Jian
College of Pharmacy, Gannan Medical University, Ganzhou 341000, China.
Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen 518118, China.
Acta Biochim Biophys Sin (Shanghai). 2024 Jul 29;56(12):1813-1822. doi: 10.3724/abbs.2024122.
The main protease (M ) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M . Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M and seven M mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M s. In addition, the crystal structures of SARS-CoV-2 M , SARS-CoV M , MERS-CoV M , and seven SARS-CoV-2 M mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M s. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.
冠状病毒的主要蛋白酶（M）在病毒复制中起关键作用，因此成为药物设计的热门靶点。PF-00835231是一种很有前景的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）M蛋白酶抑制剂。在此，我们报告了PF-00835231对SARS-CoV-2 M蛋白酶以及来自SARS-CoV-2变体的七个M蛋白酶突变体（G15S、M49I、Y54C、K90R、P132H、S46F和V186F）的抑制效力。结果证实，PF-00835231对各种冠状病毒的M蛋白酶具有广谱抑制作用。此外，还解析了SARS-CoV-2 M蛋白酶、严重急性呼吸综合征冠状病毒（SARS-CoV）M蛋白酶、中东呼吸综合征冠状病毒（MERS-CoV）M蛋白酶以及七个与PF-00835231结合的SARS-CoV-2 M蛋白酶突变体（G15S、M49I、Y54C、K90R、P132H、S46F和V186F）的晶体结构。对这些结构的详细分析揭示了抑制作用所必需的关键决定因素，并阐明了不同冠状病毒M蛋白酶的结合模式。鉴于主要蛋白酶在治疗冠状病毒感染中的重要性，对PF-00835231抑制M蛋白酶的结构见解可以加速针对不同人类冠状病毒设计具有广谱疗效的新型抗病毒药物。
