Department of Pharmaceutical Biology, University of Tübingen, 72076 Tübingen, Germany.
Nat Prod Rep. 2019 Dec 11;36(12):1654-1686. doi: 10.1039/c8np00095f.
Covering: up to 2019 Inhibitors of proteases and related enzymes have versatile applications in medicine and other areas. They are used in the clinic e.g. for the treatment of cancer, hypertension, thrombosis, diabetes as well as viral and bacterial infections. Most of these drugs are produced synthetically but a substantial part of them has been developed from or are inspired by natural products. Protease inhibitors typically mimic the peptide substrates of the target enzymes and feature specialized moieties that specifically interact with catalytic residues in the active centre. Such moieties may consist of electrophilic warheads e.g. β-lactones, Michael systems, epoxyketones or β-lactams that are attacked by active site nucleophiles and generate covalent adducts. Metalloproteinase inhibitors often contain functional groups which facilitate the chelation of active site metal ions e.g. hydroxamates, carboxylates or phosphoramidates. Other reversible protease inhibitors feature γ-amino acids or ketomethylene pseudopeptides to form stable substrate or transition state analogs. The discovery of such functional groups in natural products has been extensively exploited by medicinal chemistry to generate synthetic protease inhibitors. However, the biosynthetic principles for many of these moieties have remained obscure until recently. This review summarizes the current knowledge on the biosynthesis of important and/or structurally interesting inhibitors of proteases and related enzymes. Understanding the genetic basis that directs the formation of the specialized, activity-conferring moieties in protease inhibitors will allow targeted genome mining for the discovery of new derivatives.
截至 2019 年 抑制剂蛋白酶和相关酶在医学和其他领域有多种应用。它们在临床上被用于治疗癌症、高血压、血栓形成、糖尿病以及病毒和细菌感染。这些药物大多是合成的，但相当一部分是从天然产物中开发出来的或受其启发。蛋白酶抑制剂通常模拟靶酶的肽底物，并具有专门的部分，这些部分与活性中心的催化残基特异性相互作用。这些部分可以包括亲电弹头，例如β-内酰胺、迈克尔系统、环氧化物酮或β-内酰胺，它们被活性位点亲核试剂攻击，并生成共价加合物。金属蛋白酶抑制剂通常含有促进活性位点金属离子螯合的功能基团，例如羟肟酸、羧酸酯或膦酰胺酯。其他可逆蛋白酶抑制剂具有γ-氨基酸或酮亚甲基拟肽，以形成稳定的底物或过渡态类似物。天然产物中这些功能基团的发现被药物化学广泛用于生成合成蛋白酶抑制剂。然而，直到最近，许多这些部分的生物合成原理仍然不清楚。本文综述了重要的和/或结构有趣的蛋白酶和相关酶抑制剂的生物合成的最新知识。了解指导蛋白酶抑制剂中特殊活性赋予部分形成的遗传基础，将允许针对新衍生物的靶向基因组挖掘。
