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Controlled Inhibition of Apoptosis by Photoactivatable Caspase Inhibitors.
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2020-08-18 , DOI: 10.1016/j.chembiol.2020.08.001
Suravi Chakrabarty 1 , Steven H L Verhelst 2
Affiliation  

Caspases control regulated cell death (apoptosis), a process that is crucial in the development of multicellular organisms as well as in various diseases. In order to spatiotemporally study apoptosis, we here develop photoactivatable caspase inhibitors. These are based on cysteine-reactive acyloxymethyl ketone electrophiles connected to a peptide targeting caspases. Importantly, the aspartate crucial for recognition by caspases is caged with a photoprotecting group. Ester photocages were found to be labile, and it was critical to have a nitroindoline cage, which forms a stable amide bond with the aspartate side chain. The nitroindoline-protected inhibitors lead to an efficient turn-on of inhibitory activity after irradiation with light. They are applicable in live cells, where they prevent anti-FAS-induced apoptosis only upon irradiation. Overall, these reagents will allow a better understanding of the spatial and temporal dimensions of apoptosis in complex, dynamic systems.



中文翻译:

光活化的胱天蛋白酶抑制剂对细胞凋亡的控制性抑制。

胱天蛋白酶控制受调节的细胞死亡(细胞凋亡),这一过程在多细胞生物体的发展以及各种疾病中至关重要。为了时空研究细胞凋亡,我们在这里开发可光活化的胱天蛋白酶抑制剂。这些是基于与靶向胱天蛋白酶的肽连接的半胱氨酸反应性酰氧基甲基酮亲电子试剂。重要的是,对于被胱天蛋白酶识别至关重要的天冬氨酸被光保护基封闭。发现酯光笼不稳定,具有硝基吲哚笼至关重要,该笼与天冬氨酸侧链形成稳定的酰胺键。硝基吲哚保护的抑制剂在光照射后可有效开启抑制活性。它们适用于活细胞,在活细胞中,仅在辐射时才阻止抗FAS诱导的细胞凋亡。总体,

更新日期:2020-08-18
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