Université Victor Segalen Bordeaux 2, CNRS UMR 5084 Bio-Organic Chemistry Group, 146 rue Léo Saignat, F-33076, Bordeaux Cedex, France.
Pharm Res. 2010 Aug;27(8):1713-21. doi: 10.1007/s11095-010-0164-0. Epub 2010 May 8.
Matrix metalloproteinases (MMP) are a family of proteolytic enzymes, the expression of which in a key step of tumor progression has been better defined recently. The studies highlighted the ongoing need for very specific inhibitors, substrates or release devices designed to be selective for one or at least very few MMPs.
This report deals with the design, synthesis and in vitro evaluation of linear and especially novel cyclic peptidic moieties, embodying MMP cleavable sequences designed to answer these questions. FRET (fluorescence resonance energy transfer) labelling via chromophore-modified amino-acids was used to give access to enzyme kinetics.
Evaluation of these peptides showed that cyclisation gives rise to high specificity for certain MMP, suggesting that this approach could provide very specific MMP substrate. Moreover, cyclic structures present a very good plasma stability.
These original derivatives could allow the design of MMP-controlled delivery devices, the specificity of which will be retained in complex biological media and in vivo.
基质金属蛋白酶（MMP）是一类蛋白水解酶，其表达在肿瘤进展的关键步骤中最近得到了更好的定义。这些研究强调了对非常特异性抑制剂、底物或释放装置的持续需求，这些抑制剂、底物或释放装置旨在针对一种或至少非常少数几种 MMP 具有选择性。
本报告涉及线性和新型环状肽结构域的设计、合成和体外评价，这些结构域包含 MMP 可切割序列，旨在回答这些问题。通过发色团修饰的氨基酸进行 FRET（荧光共振能量转移）标记，以获得酶动力学信息。
这些肽的评估表明，环化导致对某些 MMP 的高特异性，这表明这种方法可以提供非常特异性的 MMP 底物。此外，环状结构具有很好的血浆稳定性。
这些原创衍生物可以设计 MMP 控制的药物释放装置，其特异性将在复杂的生物介质和体内得到保留。
