College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China.
Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201204, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Jun 26;55(8):1257-1264. doi: 10.3724/abbs.2023053.
Main protease (M ) serves as an indispensable factor in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as its constantly emerging variants and is therefore considered an attractive target for antiviral drug development. Benzothiazole-based inhibitors targeting M have recently been investigated by several groups and proven to be promising leads for coronaviral drug development. In the present study, we determine the crystal structures of a benzothiazole-based inhibitor, YH-53, bound to M mutants from SARS-CoV-2 variants of concern (VOCs) or variants of interest (VOIs), including K90R (Beta, B.1.351), G15S (Lambda, C.37), Y54C (Delta, AY.4), M49I (Omicron, BA.5) and P132H (Omicron, B.1.1.529). The structures show that the benzothiazole group in YH-53 forms a C-S covalent bond with the sulfur atom of catalytic residue Cys145 in SARS-CoV-2 M mutants. Structural analysis reveals the key molecular determinants necessary for interaction and illustrates the binding mode of YH-53 to these mutant M s. In conclusion, structural insights from this study offer more information to develop benzothiazole-based drugs that are broader spectrum, more effective and safer.
主蛋白酶 (M) 是严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 及其不断出现的变体生命周期中不可或缺的因素，因此被认为是抗病毒药物开发的有吸引力的目标。基于苯并噻唑的 M 靶向抑制剂最近已被多个研究小组研究，并被证明是冠状病毒药物开发的有前途的先导物。在本研究中，我们确定了与 SARS-CoV-2 变体关注 (VOC) 或变体感兴趣 (VOI) 的 M 突变体结合的苯并噻唑基抑制剂 YH-53 的晶体结构，包括 K90R（Beta，B.1.351）、G15S（Lambda，C.37）、Y54C（Delta，AY.4）、M49I（Omicron，BA.5）和 P132H（Omicron，B.1.1.529）。这些结构表明，YH-53 中的苯并噻唑基团与 SARS-CoV-2 M 突变体中催化残基 Cys145 的硫原子形成 C-S 共价键。结构分析揭示了与这些突变 M 相互作用所需的关键分子决定因素，并说明了 YH-53 与这些突变 M 的结合模式。总之，本研究的结构见解提供了更多信息，可用于开发更广谱、更有效和更安全的基于苯并噻唑的药物。
