Tarragó Teresa, Frutos Silvia, Rodriguez-Mias Ricard A, Giralt Ernest
Institut de Recerca Biomèdica de Barcelona, Parc Científic de Barcelona, Josep Samitier 1-5, 08028 Barcelona, Spain.
Chembiochem. 2006 May;7(5):827-33. doi: 10.1002/cbic.200500424.
Prolyl oligopeptidase is a cytosolic serine peptidase that hydrolyzes proline-containing peptides at the carboxy termini of the proline residues. This peptidase has been associated with schizophrenia, bipolar affective disorder, and related neuropsychiatric disorders and might therefore have important clinical implications. Traditional Chinese medicinal (TCM) plants provide a rich source of unexplored compounds for strategies to find novel POP inhibitors, but the traditional methodologies used to identify POP inhibitors could have some limitations when working with natural products: interference with the colorimetric or fluorimetric detection methods commonly used to screen for POP inhibitors can result in the generation of false positives or false negatives. Since NMR screening is less prone to such interference, we decided to explore the use of 19F NMR to screen for POP inhibitors. We synthesized a new 19F-labeled POP substrate--Z-Gly-Pro-Phe-4(CF3)-NH2--and used it to search for new POP inhibitors in TCM plant extracts. We identified several plants with high POP-inhibitory activity and show here that the combination of 19F NMR and TCM plant extracts is a useful tool for identifying new POP inhibitors.
脯氨酰寡肽酶是一种胞质丝氨酸肽酶，可在脯氨酸残基的羧基末端水解含脯氨酸的肽。这种肽酶与精神分裂症、双相情感障碍及相关神经精神疾病有关，因此可能具有重要的临床意义。传统中药植物为寻找新型脯氨酰寡肽酶抑制剂的策略提供了丰富的未开发化合物来源，但在处理天然产物时，用于鉴定脯氨酰寡肽酶抑制剂的传统方法可能存在一些局限性：干扰常用于筛选脯氨酰寡肽酶抑制剂的比色或荧光检测方法可能会导致产生假阳性或假阴性结果。由于核磁共振筛选较少受到此类干扰，我们决定探索使用19F核磁共振来筛选脯氨酰寡肽酶抑制剂。我们合成了一种新的19F标记的脯氨酰寡肽酶底物——Z-甘氨酰-脯氨酰-苯丙氨酸-4（三氟甲基）-NH2，并使用它在中药植物提取物中寻找新的脯氨酰寡肽酶抑制剂。我们鉴定出了几种具有高脯氨酰寡肽酶抑制活性的植物，并在此表明19F核磁共振与中药植物提取物的结合是鉴定新的脯氨酰寡肽酶抑制剂的有用工具。
