Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Pharmacol Ther. 2011 Nov;132(2):180-95. doi: 10.1016/j.pharmthera.2011.07.003. Epub 2011 Jul 23.
Caspases are proteolytic enzymes mainly involved in the induction and execution phases of apoptosis. This type of programmed cell death is an essential regulatory process required to maintain the integrity and homeostasis of multicellular organisms. Inappropriate apoptosis is attributed a key role in many human diseases, including neurodegenerative disorders, ischemic damage, autoimmune diseases and cancer. Allosteric modulation of the function of a protein occurs when the regulatory trigger, such as the binding of a small effector or inhibitor molecule, takes place some distance from the protein's active site. In recent years, several caspases have been identified that possess allosteric sites and binding of small molecule to these sites resulted in the modulation of enzyme activities. Regulation of caspase activity by small molecule allosteric modulators is believed to be of great therapeutic importance. In this review we give brief highlights on recent developments in identifying and characterizing natural and synthetic allosteric inhibitors as well as activators of caspases and discuss their potential in drug discovery and protein engineering.
半胱天冬酶是一类主要参与细胞凋亡诱导和执行阶段的蛋白水解酶。这种类型的程序性细胞死亡是维持多细胞生物完整性和体内平衡所必需的重要调节过程。凋亡异常与许多人类疾病有关，包括神经退行性疾病、缺血性损伤、自身免疫性疾病和癌症。当调节触发物（如小分子效应物或抑制剂分子的结合）发生在蛋白质活性位点的一定距离处时，蛋白质的功能就会发生变构调节。近年来，已经鉴定出几种具有变构位点的半胱天冬酶，小分子与这些位点的结合导致酶活性的调节。小分子变构调节剂对半胱天冬酶活性的调节被认为具有重要的治疗意义。在这篇综述中，我们简要介绍了鉴定和表征天然和合成的半胱天冬酶别构抑制剂和激活剂的最新进展，并讨论了它们在药物发现和蛋白质工程中的潜在应用。
