Jiang Haihai, Zou Xiaofang, Zeng Pei, Zeng Xiangyi, Zhou Xuelan, Wang Jie, Zhang Jin, Li Jian
School of Basic Medical Sciences, Nanchang University, Nanchang, 330031, China.
College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou, 341000, China.
Mol Biomed. 2023 Aug 3;4(1):23. doi: 10.1186/s43556-023-00134-2.
There is an urgent need to develop effective antiviral drugs to prevent the viral infection caused by constantly circulating SARS-CoV-2 as well as its variants. The main protease (M) of SARS-CoV-2 is a salient enzyme that plays a vital role in viral replication and serves as a fascinating therapeutic target. PF-07304814 is a covalent inhibitor targeting SARS-CoV-2 M with favorable inhibition potency and drug-like properties, thus making it a promising drug candidate for the treatment of COVID-19. We previously solved the structure of PF-07304814 in complex with SARS-CoV-2 M. However, the binding modes of PF-07304814 with Ms from evolving SARS-CoV-2 variants is under-determined. In the current study, we expressed six M mutants (G15S, K90R, M49I, S46F, V186F, and Y54C) that have been identified in Omicron variants including the recently emerged XBB.1.16 subvariant and solved the crystal structures of PF-07304814 bound to M mutants. Structural analysis provided insight into the key molecular determinants responsible for the interaction between PF-07304814 and these mutant Ms. Patterns for PF-07304814 to bind with these investigated M mutants and the wild-type M are generally similar but with some differences as revealed by detailed structural comparison. Structural insights presented in this study will inform the development of novel drugs against SARS-CoV-2 and the possible conformation changes of M mutants when bound to an inhibitor.
迫切需要开发有效的抗病毒药物，以预防由不断传播的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）及其变体引起的病毒感染。SARS-CoV-2的主要蛋白酶（M）是一种重要的酶，在病毒复制中起着至关重要的作用，是一个引人注目的治疗靶点。PF-07304814是一种靶向SARS-CoV-2 M的共价抑制剂，具有良好的抑制效力和类药性质，因此使其成为治疗新型冠状病毒肺炎（COVID-19）的有前景的候选药物。我们之前解析了PF-07304814与SARS-CoV-2 M复合物的结构。然而，PF-07304814与不断进化的SARS-CoV-2变体的M蛋白的结合模式尚不完全明确。在本研究中，我们表达了在奥密克戎变体（包括最近出现的XBB.1.16亚变体）中鉴定出的六个M突变体（G15S、K90R、M49I、S46F、V186F和Y54C），并解析了PF-07304814与M突变体结合的晶体结构。结构分析深入了解了负责PF-07304814与这些突变M蛋白相互作用的关键分子决定因素。通过详细的结构比较发现，PF-07304814与这些研究的M突变体和野生型M蛋白结合的模式总体相似，但存在一些差异。本研究中呈现的结构见解将为抗SARS-CoV-2新药的开发以及M突变体与抑制剂结合时可能的构象变化提供信息。
