化学
五肽重复序列
脚手架
基质金属蛋白酶抑制剂
组合化学
基质金属蛋白酶
基质(化学分析)
肽
生物化学
色谱法
医学
生物医学工程
作者
Tomoki Takeuchi,Yusaku Nomura,Tomoko Tamita,Rie Nishikawa,Hiroyuki Kakinuma,Naoki Kojima,Kosuke Hitaka,Yunoshin Tamura,Masafumi Kamitani,Masashi Mima,Akiko Nozoe,Masato Hayashi
标识
DOI:10.1021/acs.jmedchem.2c01698
摘要
Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule-peptide hybrid 1, the tripeptide linker {5-aminopentanoic acid [Ape(5)]-Glu-Asp} of 1 was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1' pocket-binding group. The introduction of (4S)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 (18) exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition (Ki = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life (t1/2 = 265 min).
科研通智能强力驱动
Strongly Powered by AbleSci AI