Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):1387-1402. doi: 10.1080/14756366.2020.1781107.
Aza-peptide aldehydes and ketones are a new class of reversible protease inhibitors that are specific for the proteasome and clan CD cysteine proteases. We designed and synthesised aza-Leu derivatives that were specific for the chymotrypsin-like active site of the proteasome, aza-Asp derivatives that were effective inhibitors of caspases-3 and -6, and aza-Asn derivatives that inhibited and legumains. The crystal structure of caspase-3 in complex with our caspase-specific aza-peptide methyl ketone inhibitor with an aza-Asp residue at P1 revealed a covalent linkage between the inhibitor carbonyl carbon and the active site cysteinyl sulphur. Aza-peptide aldehydes and ketones showed no cross-reactivity towards cathepsin B or chymotrypsin. The initial selectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.
氮杂肽醛和酮是一类新的可逆蛋白酶抑制剂，特异性针对蛋白酶体和 CD 族半胱氨酸蛋白酶。我们设计并合成了针对蛋白酶体糜蛋白酶样活性位点的特异性氮杂亮氨酸衍生物、有效的 caspase-3 和 caspase-6 抑制剂氮杂天冬氨酸衍生物，以及抑制和 legumains 的氮杂天冬酰胺衍生物。与我们的 caspase 特异性氮杂肽甲基酮抑制剂的 caspase-3 晶体结构复合物中，P1 位的氮杂天冬氨酸残基与抑制剂羰基碳之间形成了共价键。氮杂肽醛和酮对组织蛋白酶 B 或糜蛋白酶没有交叉反应。这些抑制剂的初始选择性使它们成为进一步开发成治疗剂的候选药物，以潜在地治疗多发性骨髓瘤、神经退行性疾病和寄生虫感染。
