Groborz Katarzyna, Gonzalez Ramirez Monica L, Snipas Scott J, Salvesen Guy S, Drąg Marcin, Poręba Marcin
Department of Bioorganic Chemistry, Faculty of Chemistry, Wroclaw University of Science and Technology, Wyb. Wyspianskiego 27, 50-370, Wroclaw, Poland.
NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
Cell Death Differ. 2020 Feb;27(2):451-465. doi: 10.1038/s41418-019-0364-z. Epub 2019 Jun 17.
Caspases participate in regulated cell death mechanisms and are divided into apoptotic and proinflammatory caspases. The main problem in identifying the unique role of a particular caspase in the mechanisms of regulated cell death is their overlapping substrate specificity; caspases recognize and hydrolyze similar peptide substrates. Most studies focus on examining the non-prime sites of the caspases, yet there is a need for novel and more precise chemical tools to identify the molecular participants and mechanisms of programmed cell death pathways. Therefore, we developed an innovative chemical approach that examines the prime area of the caspase active sites. This method permits the agile parallel solid-phase synthesis of caspase inhibitors with a high yield and purity. Using synthesized compounds we have shown the similarities and differences in the prime area of the caspase active site and, as a proof of concept, we demonstrated the exclusive role of caspase-8 in necroptosis.
半胱天冬酶参与调控细胞死亡机制，可分为凋亡性半胱天冬酶和促炎性半胱天冬酶。确定特定半胱天冬酶在调控细胞死亡机制中的独特作用的主要问题在于它们重叠的底物特异性；半胱天冬酶识别并水解相似的肽底物。大多数研究集中于检查半胱天冬酶的非切割位点，然而，需要新颖且更精确的化学工具来识别程序性细胞死亡途径的分子参与者和机制。因此，我们开发了一种创新的化学方法，用于检查半胱天冬酶活性位点的切割区域。该方法允许以高产率和高纯度灵活地平行固相合成半胱天冬酶抑制剂。使用合成化合物，我们展示了半胱天冬酶活性位点切割区域的异同，并且作为概念验证，我们证明了半胱天冬酶-8在坏死性凋亡中的独特作用。
