Sorbonne University, Faculty of Sciences and Engineering, IBPS, UMR 8256 CNRS-UPMC, ERL INSERM U1164, Biological Adaptation and Ageing, F-75252 Paris, France.
Sorbonne University, Faculty of Sciences and Engineering, IMPMC, UMR 7590 CNRS-UPMC-MNHN-IRD, F-75252 Paris, France.
Biol Chem. 2018 Sep 25;399(9):1073-1078. doi: 10.1515/hsz-2017-0336.
The activity of kallikrein-related peptidase 6 (KLK6) is deregulated in various diseases such as cancer and neurodegenerative diseases. KLK6 is thus considered as an attractive therapeutical target. In this short report, we depict some novel findings on the regulation of the KLK6 activity. Namely, we identified mechanism-based inhibitors (suicide substrates) from an in-house library of 6-substituted coumarin-3-carboxylate derivatives. In addition, a molecular dynamics study evidenced the allosteric behavior of KLK6 similar to that previously observed for some trypsin-like serine proteases. This allosteric behavior together with the coumarinic scaffold bring new opportunities for the design of KLK6 potent activity modulators, useful as therapeutics or activity-based probes.
激肽释放酶相关肽酶 6（KLK6）的活性在各种疾病中失调，如癌症和神经退行性疾病。因此，KLK6 被认为是一个有吸引力的治疗靶点。在本短报告中，我们描述了一些关于 KLK6 活性调节的新发现。即，我们从内部 6-取代香豆素-3-羧酸酯衍生物文库中鉴定出基于机制的抑制剂（自杀底物）。此外，分子动力学研究表明 KLK6 具有变构行为，类似于先前观察到的某些胰蛋白酶样丝氨酸蛋白酶。这种变构行为以及香豆素支架为 KLK6 有效活性调节剂的设计带来了新的机会，可作为治疗剂或基于活性的探针。
