School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Int J Mol Sci. 2023 May 11;24(10):8633. doi: 10.3390/ijms24108633.
The papain-like protease (PL) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a critical role in the proteolytic processing of viral polyproteins and the dysregulation of the host immune response, providing a promising therapeutic target. Here, we report the structure-guide design of novel peptidomimetic inhibitors covalently targeting SARS-CoV-2 PL. The resulting inhibitors demonstrate submicromolar potency in the enzymatic assay (IC = 0.23 μM) and significant inhibition of SARS-CoV-2 PL in the HEK293T cells using a cell-based protease assay (EC = 3.61 μM). Moreover, an X-ray crystal structure of SARS-CoV-2 PL in complex with compound confirms the covalent binding of the inhibitor to the catalytic residue cysteine 111 (C111) and emphasizes the importance of interactions with tyrosine 268 (Y268). Together, our findings reveal a new scaffold of SARS-CoV-2 PL inhibitors and provide an attractive starting point for further optimization.
严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的木瓜蛋白酶样蛋白酶 (PL) 在病毒多蛋白的蛋白水解加工和宿主免疫反应失调中发挥着关键作用，为治疗提供了有前景的靶点。在这里，我们报告了针对 SARS-CoV-2 PL 的新型肽模拟物抑制剂的结构导向设计。所得抑制剂在酶测定中表现出亚微摩尔的效力（IC = 0.23 μM），并在使用基于细胞的蛋白酶测定法的 HEK293T 细胞中对 SARS-CoV-2 PL 具有显著的抑制作用（EC = 3.61 μM）。此外，SARS-CoV-2 PL 与化合物的 X 射线晶体结构证实了抑制剂与催化残基半胱氨酸 111 (C111) 的共价结合，并强调了与酪氨酸 268 (Y268) 相互作用的重要性。总之，我们的研究结果揭示了 SARS-CoV-2 PL 抑制剂的新骨架，并为进一步优化提供了有吸引力的起点。
