The University of Tennessee Health Science Center , Memphis, TN , USA
Expert Opin Ther Pat. 2015 Jan;25(1):17-31. doi: 10.1517/13543776.2014.982534. Epub 2014 Nov 15.
Calpain is a family of cysteine proteases found in eukaryotes and a few bacteria. There is considerable interest in the search for calpain inhibitors because the enzyme has been implicated in several diseases including ocular disorders, neurodegenerative disorders, metabolic disorders and cancer.
An overview of calpain inhibitors disclosed between 2012 and 2014 is presented. Among these are epoxysuccinates, dipeptide imaging agents, macrocyclic inhibitors, α-helical peptidomimetic inhibitors, carboxamides, 5-azolones and α-mercaptoacrylates. Additionally, preclinical studies of calpain inhibitors in pathologies such blood disorders, ocular disorders, neurological disorders and muscle disorders are discussed.
Major advances made in calpain inhibitor research between 2012 and 2014 include: i) the discovery of cytosolic-stable carboxamide calpain inhibitors; ii) synthesis of epoxysuccinates with excellent bioavailability; iii) disclosure of the X-ray crystal structures of novel α-mercaptoacrylates bound to the pentaEF hand region from human calpain; and iv) disclosure of calpain inhibitors as anti-sickling agents. Several calpain inhibitors were reported but limited effort was directed towards the discovery of calpain isoform selective agents, which continues to dampen the therapeutic potential of calpain inhibitors.
钙蛋白酶是真核生物和少数细菌中发现的半胱氨酸蛋白酶家族。由于该酶与几种疾病（包括眼部疾病、神经退行性疾病、代谢疾病和癌症）有关，因此人们对钙蛋白酶抑制剂的研究产生了浓厚的兴趣。
本文对 2012 年至 2014 年间披露的钙蛋白酶抑制剂进行了概述。其中包括环氧化物琥珀酸盐、二肽成像剂、大环抑制剂、α-螺旋肽模拟抑制剂、羧酰胺、5-唑酮和α-巯基丙烯酸盐。此外，还讨论了钙蛋白酶抑制剂在血液疾病、眼部疾病、神经疾病和肌肉疾病等病理中的临床前研究。
2012 年至 2014 年间，钙蛋白酶抑制剂研究取得了重大进展，包括：i）发现细胞溶质稳定的羧酰胺钙蛋白酶抑制剂；ii）合成具有优异生物利用度的环氧化物琥珀酸盐；iii）披露新型α-巯基丙烯酸盐与来自人钙蛋白酶的五 EF 手区结合的 X 射线晶体结构；iv）披露钙蛋白酶抑制剂作为抗镰状细胞药物。报道了几种钙蛋白酶抑制剂，但在发现钙蛋白酶同工型选择性抑制剂方面的努力有限，这继续抑制了钙蛋白酶抑制剂的治疗潜力。
