仿生酰基转移酶对环氧化酶-1 的催化共价抑制。
Catalytic covalent inhibition of cyclooxygenase-1 by a biomimetic acyltransferase.
机构信息
University of Delaware, 102 Brown Laboratory, Newark, DE 19716, USA.
University of Delaware, 102 Brown Laboratory, Newark, DE 19716, USA.
出版信息
Bioorg Med Chem. 2022 Oct 15;72:116973. doi: 10.1016/j.bmc.2022.116973. Epub 2022 Aug 27.
Covalent binding enzyme inhibitors have grown in acceptance in therapeutic discovery. Several recent examples of protein-targeting acyl-transfer catalysts covalently modify protein targets in cellular systems but generally do not affect protein function. In this study, a small molecule has been developed for the first time that can achieve catalytic covalent inhibition of the inflammatory response enzyme, cyclooxygenase-1, in cells using only endogenous acetyl-CoA as a co-substrate. By utilizing a catalytic inhibitor which can self-regenerate, a sustained inhibitory response is achieved in cells compared to the analogous non-catalytic covalent cyclooxygenase antagonist, acetylsalicylic acid (aspirin).
共价键酶抑制剂在治疗发现中越来越受到重视。最近有几个例子表明，靶向蛋白质的酰基转移催化剂可以在细胞系统中共价修饰蛋白质靶标，但通常不会影响蛋白质功能。在这项研究中，首次开发出一种小分子，它可以仅使用内源性乙酰辅酶 A 作为共底物，在细胞中实现对炎症反应酶环加氧酶-1 的催化共价抑制。通过利用可以自我再生的催化抑制剂，与类似的非催化共价环氧化酶拮抗剂乙酰水杨酸（阿司匹林）相比，在细胞中实现了持续的抑制反应。
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