Abstract

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 S. mansoni and I. ricinus 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 in vitro selectivity of these inhibitors makes them suitable candidates for further development into therapeutic agents to potentially treat multiple myeloma, neurodegenerative diseases, and parasitic infections.

摘要

氮杂-肽醛和酮是一类新的可逆蛋白酶抑制剂，对蛋白酶体和氏族CD半胱氨酸蛋白酶具有特异性。我们设计并合成了对蛋白酶体的胰凝乳蛋白酶样活性位点特异的aza-Leu衍生物，可有效抑制caspases-3和-6的aza-Asp衍生物，以及可抑制曼氏梭菌和I的aza-Asn衍生物。蓖麻毒素豆。caspase-3的晶体结构与我们的caspase特异的aza-肽甲基酮抑制剂在P1处具有aza-Asp残基相结合，揭示了抑制剂羰基碳和活性位半胱氨酸硫之间的共价键。氮杂肽醛和酮对组织蛋白酶B或胰凝乳蛋白酶没有交叉反应性。最初的这些抑制剂的体外选择性使其成为进一步发展成治疗剂的潜在候选药物，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。