Katunuma N, Matsui A, Inubushi T, Murata E, Kakegawa H, Ohba Y, Turk D, Turk V, Tada Y, Asao T
Institute for Health Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan.
Biochem Biophys Res Commun. 2000 Jan 27;267(3):850-4. doi: 10.1006/bbrc.1999.1953.
We found that pyridoxal phosphate shows considerable inhibition of cathepsins. CLIK-071, in which the phosphate ester of position 3 of pyridoxal phosphate was replaced by propionate, strongly inhibited cathepsin B. Three new types of synthetic pyridoxal propionate derivatives showing specific inhibition of cathepsin K were developed. New synthetic pyridoxal propionate derivatives, -162, -163, and -164, in which the methyl arm of position 6 of CLIK-071 was additionally modified, strongly inhibited cathepsin K and cathepsin S weakly, but other cathepsins were not inhibited. CLIK-166, in which the position 4 aldehyde of CLIK-071 is replaced by a vinyl radical and position 5 is additionally modified, showed cathepsin K-specific inhibition at 10(-5) M. Pit formation due to bone collagen degradation by cathepsin K of rat osteoclasts was specifically suppressed by administration of CLIK-164, but not by inhibitors of cathepsin L or B.
我们发现磷酸吡哆醛对组织蛋白酶有显著抑制作用。CLIK-071中，磷酸吡哆醛3位的磷酸酯被丙酸取代，它强烈抑制组织蛋白酶B。开发了三种新型的对组织蛋白酶K有特异性抑制作用的合成吡哆醛丙酸酯衍生物。新型合成吡哆醛丙酸酯衍生物-162、-163和-164，其中CLIK-071 6位的甲基臂被额外修饰，它们强烈抑制组织蛋白酶K，对组织蛋白酶S有较弱抑制作用，但不抑制其他组织蛋白酶。CLIK-166中，CLIK-071的4位醛基被乙烯基取代且5位被额外修饰，它在10(-5) M时表现出对组织蛋白酶K的特异性抑制作用。给予CLIK-164可特异性抑制大鼠破骨细胞的组织蛋白酶K导致的骨胶原降解引起的凹坑形成，但组织蛋白酶L或B的抑制剂则无此作用。
