La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
J Biol Chem. 2013 May 10;288(19):13885-96. doi: 10.1074/jbc.M113.460030. Epub 2013 Apr 2.
Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone.
Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity.
An analog of MCoTI-II is one of the most potent inhibitors of matriptase.
These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential. The type II transmembrane serine protease matriptase is a key activator of multiple signaling pathways associated with cell proliferation and modification of the extracellular matrix. Deregulated matriptase activity correlates with a number of diseases, including cancer and hence highly selective matriptase inhibitors may have therapeutic potential. The plant-derived cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), is a promising drug scaffold with potent matriptase inhibitory activity. In the current study we have analyzed the structure-activity relationships of SFTI-1 and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II), a structurally divergent trypsin inhibitor from Momordica cochinchinensis that also contains a cyclic backbone. We show that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, have decreased trypsin affinity, whereas several mutations either maintain or result in enhanced matriptase inhibitory activity. These intriguing results were used to design one of the most potent matriptase inhibitors known to date with a 290 pm equilibrium dissociation constant, and provide the first indication on how to modulate affinity for matriptase over trypsin in cyclic peptides. This information might be useful for the design of more selective and therapeutically relevant inhibitors of matriptase.
向日葵胰蛋白酶抑制剂-1（SFTI-1）和苦瓜胰蛋白酶抑制剂-II（MCoTI-II）是具有环状骨架的强效蛋白酶抑制剂。
阐明 SFTI-1 和 MCoTI-II 的结构-活性关系，用于设计具有增强抑制活性的抑制剂。
MCoTI-II 的类似物是基质金属蛋白酶丝氨酸 2（matriptase）的最有效抑制剂之一。
这些结果为设计具有治疗潜力的基质金属蛋白酶丝氨酸 2 选择性肽抑制剂提供了坚实的基础。II 型跨膜丝氨酸蛋白酶 matriptase 是与细胞增殖和细胞外基质修饰相关的多种信号通路的关键激活剂。失调的 matriptase 活性与许多疾病相关，包括癌症，因此高度选择性的 matriptase 抑制剂可能具有治疗潜力。来自向日葵的植物衍生环状肽 SFTI-1 是一种具有强效 matriptase 抑制活性的有前途的药物支架。在本研究中，我们分析了 SFTI-1 和 Momordica cochinchinensis 胰蛋白酶抑制剂-II（MCoTI-II）的结构-活性关系，MCoTI-II 是一种结构上不同的来自 Momordica cochinchinensis 的胰蛋白酶抑制剂，也含有环状骨架。我们表明，MCoTI-II 是比 SFTI-1 更强效的 matriptase 抑制剂，并且两种肽的所有丙氨酸突变体，使用位置扫描突变生成，都降低了胰蛋白酶亲和力，而一些突变要么保持要么导致增强的 matriptase 抑制活性。这些有趣的结果被用于设计迄今为止已知的最有效的基质金属蛋白酶丝氨酸 2 抑制剂之一，其平衡解离常数为 290 pm，并首次表明如何在环状肽中调节对基质金属蛋白酶丝氨酸 2 的亲和力而不是胰蛋白酶。这些信息可能有助于设计更具选择性和更具治疗相关性的基质金属蛋白酶丝氨酸 2 抑制剂。
