巯基靶向头（SAr）在半胱氨酸蛋白酶中的取代诱导的机制转换。

Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg 5, 55128 Mainz, Germany.

Department of Chemistry, University of Mainz, Duesbergweg 10-14, 55128 Mainz, Germany.

Molecules. 2024 Jun 4;29(11):2660. doi: 10.3390/molecules29112660.

The aim of this study was to investigate the transition from non-covalent reversible over covalent reversible to covalent irreversible inhibition of cysteine proteases by making delicate structural changes to the warhead scaffold. To this end, dipeptidic rhodesain inhibitors with different -terminal electrophilic arenes as warheads relying on the SAr mechanism were synthesized and investigated. Strong structure-activity relationships of the inhibition potency, the degree of covalency, and the reversibility of binding on the arene substitution pattern were found. The studies were complemented and substantiated by molecular docking and quantum-mechanical calculations of model systems. Furthermore, the improvement in the membrane permeability of peptide esters in comparison to their corresponding carboxylic acids was exemplified.

本研究旨在通过对弹头支架进行精细的结构改变，研究半胱氨酸蛋白酶从非共价可逆、共价可逆到共价不可逆抑制的转变。为此，我们合成并研究了依赖 SAr 机制、不同 -末端亲电芳基作为弹头的二肽 rhodesain 抑制剂。我们发现芳基取代模式对抑制效力、共价程度和结合可逆性具有强烈的构效关系。这些研究得到了分子对接和模型系统量子力学计算的补充和证实。此外，我们还举例说明了与相应羧酸相比，肽酯的膜通透性得到了改善。