Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration of action, poor protease selectivity, and low blood-brain barrier (BBB) permeability, which altogether limit their potential as drugs. Here, we describe the structure-based design of the first irreversible, selective, and brain-permeable POP inhibitors. At low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, bothin vitroand in human cells. More importantly, they are >1,000-fold selective against two family-related proteases (DPPIV and FAP) and display high BBB permeability, as shown in both lipid membranes and MDCK cells.

中文翻译：

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有针对性的共价抑制脯氨酰寡肽酶（POP）：磺酰氟肽模拟物的发现。

脯氨酰寡肽酶（POP）是一种在大脑中高度表达的丝氨酸蛋白酶，最近已成为治疗认知和神经退行性疾病的诱人治疗靶标。然而，大多数报道的抑制剂具有作用时间短，蛋白酶选择性差和血脑屏障（BBB）渗透性低的缺点，这完全限制了它们作为药物的潜力。在这里，我们描述了第一个不可逆的，选择性的和脑可渗透的POP抑制剂的基于结构的设计。在低纳摩尔浓度下，这些共价拟肽在体外和在人细胞中都能快速，特异性和持续地灭活POP。更重要的是，它们对两种家族相关蛋白酶（DPPIV和FAP）的选择性> 1,000倍，并且显示出高的BBB渗透性，如脂膜和MDCK细胞中所示。