Flury Philipp, Breidenbach Julian, Krüger Nadine, Voget Rabea, Schäkel Laura, Si Yaoyao, Krasniqi Vesa, Calistri Sara, Olfert Matthias, Sylvester Katharina, Rocha Cheila, Ditzinger Raphael, Rasch Alexander, Pöhlmann Stefan, Kronenberger Thales, Poso Antti, Rox Katharina, Laufer Stefan A, Müller Christa E, Gütschow Michael, Pillaiyar Thanigaimalai
Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany.
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn 53121, Germany.
ACS Pharmacol Transl Sci. 2024 Jan 19;7(2):493-514. doi: 10.1021/acsptsci.3c00313. eCollection 2024 Feb 9.
Cathepsins (Cats) are proteases that mediate the successful entry of SARS-CoV-2 into host cells. We designed and synthesized a tailored series of 21 peptidomimetics and evaluated their inhibitory activity against human cathepsins L, B, and S. Structural diversity was realized by combinations of different C-terminal warhead functions and N-terminal capping groups, while a central Leu-Phe fragment was maintained. Several compounds were identified as promising cathepsin L and S inhibitors with values in the low nanomolar to subnanomolar range, for example, the peptide aldehydes and (, 2.67 nM, CatL; 0.455 nM, CatS; , 1.76 nM, CatL; 0.512 nM, CatS). The compounds' inhibitory activity against the main protease of SARS-CoV-2 (M) was additionally investigated. Based on the results at CatL, CatS, and M, selected inhibitors were subjected to investigations of their antiviral activity in cell-based assays. In particular, the peptide nitrile exhibited promising antiviral activity with an EC value of 38.4 nM in Calu-3 cells without showing cytotoxicity. High metabolic stability and favorable pharmacokinetic properties make suitable for further preclinical development.
组织蛋白酶（Cats）是介导严重急性呼吸综合征冠状病毒2（SARS-CoV-2）成功进入宿主细胞的蛋白酶。我们设计并合成了一系列定制的21种拟肽，并评估了它们对人组织蛋白酶L、B和S的抑制活性。通过不同的C端弹头功能和N端封端基团的组合实现结构多样性，同时保留一个中心亮氨酸-苯丙氨酸片段。几种化合物被鉴定为有前景的组织蛋白酶L和S抑制剂，其抑制常数（Ki）值在低纳摩尔到亚纳摩尔范围内，例如，肽醛 和 （，组织蛋白酶L的Ki为2.67 nM；组织蛋白酶S的Ki为0.455 nM；，组织蛋白酶L的Ki为1.76 nM；组织蛋白酶S的Ki为0.512 nM）。此外，还研究了这些化合物对SARS-CoV-2主要蛋白酶（M）的抑制活性。基于对组织蛋白酶L、组织蛋白酶S和M的研究结果，对选定的抑制剂进行了基于细胞试验的抗病毒活性研究。特别是，肽腈 在Calu-3细胞中表现出有前景的抗病毒活性，其半数有效浓度（EC）值为38.4 nM，且未显示出细胞毒性。高代谢稳定性和良好的药代动力学性质使得 适合进一步的临床前开发。
