Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, College of Pharmacy , Memphis, Tennessee, United States.
Expert Opin Ther Pat. 2020 Sep;30(9):659-675. doi: 10.1080/13543776.2020.1797678. Epub 2020 Aug 25.
Calpain is a cytosolic proteinase that regulates of a wide range of physiological functions. The enzyme has been implicated in various pathological conditions including neurodegenerative disorders, cardiovascular disorders, cancer, and several other diseases. Therefore, calpain inhibitors are of interest as therapeutic agents and have been studied in preclinical models of several diseases in which the enzyme has been implicated.
Calpain inhibitors that were disclosed over the last 5 years (2015-2019) include calpastatin-based peptidomimetics; thalassospiramide lipopeptides; disulfide analogs of alpha-mercaptoacrylic acids; allosteric modulators; azoloimidazolidenones; and macrocyclic/non-macrocyclic carboxamides. The effectiveness of some of the inhibitors in preclinical animal models is discussed.
Significant milestones that were made over this time frame include: a) disclosure of novel blood-brain barrier (BBB) permeable calpastatin analogs as calpain inhibitors; b) disclosure that potent calpain inhibitors can be obtained by targeting the hydrophobic pockets on chain A of PEF(S) of the small subunit of calpain; c) use of PEF(S) (PDB ID: 4WQ2) in virtual screening to identify novel structurally diverse calpain inhibitors; and d) mitigation of the metabolic instability of the alpha-ketoamide warhead of calpain inhibitors.
钙蛋白酶是一种细胞溶质蛋白水解酶，可调节多种生理功能。该酶与多种病理状况有关，包括神经退行性疾病、心血管疾病、癌症和其他几种疾病。因此，钙蛋白酶抑制剂作为治疗剂具有重要意义，并已在涉及该酶的几种疾病的临床前模型中进行了研究。
过去 5 年（2015-2019 年）披露的钙蛋白酶抑制剂包括基于钙蛋白酶抑制蛋白的肽模拟物；海洋螺旋菌脂肽；α-巯基丙烯酸的二硫键类似物；别构调节剂；氮唑并咪唑烷酮；以及大环/非大环酰胺。讨论了一些抑制剂在临床前动物模型中的有效性。
在这段时间内取得了重大进展，包括：a）披露了新型血脑屏障（BBB）可渗透的钙蛋白酶抑制蛋白模拟物作为钙蛋白酶抑制剂；b）披露通过靶向钙蛋白酶小亚基 PEF（S）的链 A 上的疏水性口袋可以获得有效的钙蛋白酶抑制剂；c）使用 PEF（S）（PDB ID：4WQ2）进行虚拟筛选，以鉴定新型结构多样的钙蛋白酶抑制剂；以及 d）减轻钙蛋白酶抑制剂的α-酮酰胺弹头的代谢不稳定性。
