D-Val22 containing human big endothelin-1 analog, [D-Val22]Big ET-1[16-38], inhibits the endothelin converting enzyme.
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.
Morita
A
A
Laboratory of Nutritional Biochemistry, School of Food and Nutritional Sciences, University of Shizuoka, Japan.
Nomizu
M
M
Okitsu
M
M
Horie
K
K
Yokogoshi
H
H
Roller
P P
PP
D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002417:Cattle; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008666:Metalloendopeptidases; D008969:Molecular Sequence Data; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000737:chemistry / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D014633:Valine / Q000737:chemistry*
D019332:Endothelin-1; D016232:Endothelins; D010455:Peptides; D011498:Protein Precursors; C089858:big endothelin-1(16-38), valine(22)-; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D014633:Valine; D004298:Dopamine