School of Chemistry & Physics, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Curr Top Med Chem. 2010;10(3):270-93. doi: 10.2174/156802610790725489.
The physiological roles of calpains are discussed, as are the associated pathological disorders that result from their over-activation. We also present practical information for establishing functional inhibition assays and an overview of X-ray crystal structures of calpain-inhibitor complexes to aid inhibitor design. These structures reveal the expected extended beta-strand conformation for the inhibitor backbone, a geometry that has been engineered into inhibitors with the introduction of either an N-terminal heterocycle or a macrocycle that links the P(1) and P(3) residues. The structure and function of all the main classes of inhibitors are reviewed, with most examples being classified according to the nature of the C-terminal reactive warhead group that reacts with the active site cysteine of calpains. These inhibitor classes include epoxysuccinate derivatives, aldehydes, aldehyde prodrugs (hemiacetals) and alpha-keto carbonyl compounds. Inhibitors derived from the endogenous inhibitor calpastatin and examples lacking a warhead, are now known and these are also discussed.
钙蛋白酶的生理作用，以及它们过度激活所导致的相关病理紊乱，也在本文中进行了讨论。我们还提供了关于建立功能抑制测定的实用信息，以及钙蛋白酶抑制剂复合物的 X 射线晶体结构概述，以帮助抑制剂的设计。这些结构揭示了抑制剂骨架中预期的扩展β-折叠构象，这种几何形状已经通过在 N 端引入杂环或连接 P(1)和 P(3)残基的大环而被引入到抑制剂中。本文综述了所有主要抑制剂类别的结构和功能，大多数例子都是根据与钙蛋白酶的活性位点半胱氨酸反应的 C 末端反应性弹头基团的性质进行分类的。这些抑制剂类别包括环氧琥珀酸盐衍生物、醛类、醛前药（半缩醛）和α-酮羰基化合物。现在已经知道并讨论了来源于内源性抑制剂钙蛋白酶抑制剂和缺乏弹头的抑制剂。
