Sasaki T, Kishi M, Saito M, Tanaka T, Higuchi N, Kominami E, Katunuma N, Murachi T
Department of Clinical Science and Laboratory Medicine, Kyoto University Faculty of Medicine, Japan.
J Enzyme Inhib. 1990;3(3):195-201. doi: 10.3109/14756369009035837.
Eight different di- and tripeptidyl aldehyde derivatives, each having at its C-terminus an aldehyde analog of L-norleucine, L-methionine, or L-phenylalanine with a preceding L-leucine residue, were synthesized and tested for their inhibitory effects on several serine and cysteine endopeptidases. These compounds showed almost no inhibition of trypsin, and only weak inhibition of alpha-chymotrypsin and cathepsin H, while they exhibited marked inhibition of cathepsin B less than calpain II congruent to calpain I less than cathepsin L, being stronger in this order. The mode of inhibition of these cysteine proteinases was competitive for the peptide substrate used and inhibitor constants (Ki) were calculated from the Dixon plot. The best inhibitors found were: 4-phenyl-butyryl-Leu-Met-H for calpain I (Ki, 36 nM) and calpain II (Ki, 50 nM); acetyl-Leu-Leu-nLeu-H for cathepsin L (Ki, 0.5 nM); acetyl-Leu-Leu-Met-H for cathepsin B (Ki, 100 nM).
合成了八种不同的二肽基和三肽基醛衍生物，每种衍生物在其C末端都有一个L-正亮氨酸、L-甲硫氨酸或L-苯丙氨酸的醛类似物，且前面有一个L-亮氨酸残基，并测试了它们对几种丝氨酸和半胱氨酸内肽酶的抑制作用。这些化合物对胰蛋白酶几乎没有抑制作用，对α-胰凝乳蛋白酶和组织蛋白酶H只有微弱的抑制作用，而它们对组织蛋白酶B的抑制作用明显，对钙蛋白酶II的抑制作用小于对钙蛋白酶I的抑制作用，对组织蛋白酶L的抑制作用最小，抑制强度依次增强。这些半胱氨酸蛋白酶的抑制模式对所用的肽底物具有竞争性，并根据Dixon图计算抑制常数（Ki）。发现的最佳抑制剂为：对钙蛋白酶I（Ki，36 nM）和钙蛋白酶II（Ki，50 nM）为4-苯基-丁酰基-Leu-Met-H；对组织蛋白酶L（Ki，0.5 nM）为乙酰基-Leu-Leu-nLeu-H；对组织蛋白酶B（Ki，100 nM）为乙酰基-Leu-Leu-Met-H。
