De Decker An, Vliegen Gwendolyn, Van Rompaey Dries, Peeraer Anke, Bracke An, Verckist Line, Jansen Koen, Geiss-Friedlander Ruth, Augustyns Koen, De Winter Hans, De Meester Ingrid, Lambeir Anne-Marie, Van der Veken Pieter
Laboratory of Medicinal Chemistry (UAMC), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk (Antwerp), Belgium.
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk (Antwerp), Belgium.
ACS Med Chem Lett. 2019 Jul 9;10(8):1173-1179. doi: 10.1021/acsmedchemlett.9b00191. eCollection 2019 Aug 8.
Fibroblast activation protein (FAP) is a proline-selective serine protease. It is hardly expressed in healthy adult tissue but upregulated in tissue remodeling sites associated with several diseases including epithelial cancer types, atherosclerosis, arthritis and fibrosis. Ongoing research aims at clinical implementation of FAP as a biomarker for these diseases. Several immunochemical methods that quantify FAP expression have been reported. An alternative/complementary approach focuses on quantification of FAP's enzymatic activity. Developing an activity-based assay for FAP has nonetheless proven challenging because of selectivity issues with respect to prolyl oligopeptidase (PREP). Here, we present substrate-type FAP probes that are structurally derived from a FAP-inhibitor (UAMC1110) that we published earlier. Both cleavage efficiency and FAP-selectivity of the best compounds in the series equal or surpass the most advanced peptide-based FAP substrates reported to date. Finally, proof-of-concept is provided that 4-aminonaphthol containing probes can spatially localize FAP activity in biological samples.
成纤维细胞活化蛋白（FAP）是一种脯氨酸选择性丝氨酸蛋白酶。它在健康成人组织中几乎不表达，但在与多种疾病相关的组织重塑部位上调，这些疾病包括上皮癌类型、动脉粥样硬化、关节炎和纤维化。正在进行的研究旨在将FAP作为这些疾病的生物标志物用于临床。已经报道了几种定量FAP表达的免疫化学方法。一种替代/补充方法侧重于定量FAP的酶活性。然而，由于脯氨酰寡肽酶（PREP）的选择性问题，开发一种基于活性的FAP检测方法已被证明具有挑战性。在这里，我们展示了底物型FAP探针，其结构源自我们之前发表的一种FAP抑制剂（UAMC1110）。该系列中最佳化合物的切割效率和FAP选择性均等于或超过了迄今为止报道的最先进的基于肽的FAP底物。最后，提供了概念验证，即含有4-氨基萘酚的探针可以在生物样品中对FAP活性进行空间定位。
