Morita A, Nomizu M, Okitsu M, Horie K, Yokogoshi H, Roller P P
Laboratory of Nutritional Biochemistry, School of Food and Nutritional Sciences, University of Shizuoka, Japan.
FEBS Lett. 1994 Oct 10;353(1):84-8. doi: 10.1016/0014-5793(94)01012-9.
Endothelin converting enzyme (ECE) is essential for generation of the biological effects of endothelin-1 (ET-1) from a precursor, big endothelin-1 (Big ET-1). We synthesized four analogs of human Big ET-1[16-38], substituted with single D-amino acids at P1, P2, P1' and P2' positions. ECE activity was determined using an ET-1 specific radioimmunoassay system. None of the D-amino acid containing Big ET-1 analogs were apparently cleaved by ECE, however, one of the synthetic peptides, [D-Val22]Big ET-1[16-38], strongly inhibited the ECE activity. Furthermore, when this D-Val22 containing peptide was preadministered to rat striatum, it was found to inhibit the dopamine release induced by Big ET-1. This result suggests that the D-Val22 containing peptide inhibits the ECE activity in vivo. The D-Val22 containing inhibitor offers hope of developing more potent and highly specific ECE inhibitors of therapeutic significance.
内皮素转化酶（ECE）对于从前体大内皮素-1（Big ET-1）生成内皮素-1（ET-1）的生物学效应至关重要。我们合成了四种人Big ET-1[16-38]类似物，它们在P1、P2、P1'和P2'位置被单个D-氨基酸取代。使用ET-1特异性放射免疫分析系统测定ECE活性。含D-氨基酸的Big ET-1类似物均未被ECE明显切割，然而，其中一种合成肽[D-Val22]Big ET-1[16-38]强烈抑制ECE活性。此外，当将这种含D-Val22的肽预先给予大鼠纹状体时，发现它能抑制Big ET-1诱导的多巴胺释放。该结果表明含D-Val22的肽在体内抑制ECE活性。含D-Val22的抑制剂为开发具有治疗意义的更有效且高度特异性的ECE抑制剂带来了希望。
