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Cyclic insulin‐regulated aminopeptidase (IRAP)/AT 4 receptor ligands
Author(s) -
Axén Andreas,
Lindeberg Gunnar,
Demaegdt Heidi,
Vauquelin Georges,
Karlén Anders,
Hallberg Mathias
Publication year - 2006
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.782
Subject(s) - chemistry , aminopeptidase , enzyme , peptide , angiotensin ii , stereochemistry , angiotensin receptor , receptor , ligand (biochemistry) , biochemistry , amino acid , leucine
The angiotensin IV receptor (AT 4 receptor) is the insulin‐regulated aminopeptidase enzyme (IRAP, EC 3.4.11.3). This membrane‐spanning enzyme belongs to the M1 family of zinc‐dependent metallo‐peptidases. It has been proposed that AT 4 receptor ligands exert their physiological effects by binding to the active site of IRAP and thereby inhibiting the catalytic activity of the enzyme. The biological activity of a large series of linear angiotensin IV analogs was previously disclosed. Herein, the synthesis and biological evaluation of a series of angiotensin IV analogs, encompassing macrocyclic ring systems of different sizes, are presented. It is demonstrated that disulfide cyclizations of angiotensin IV can deliver ligands with high IRAP/AT 4 receptor affinity. One ligand, with an 11‐membered ring system ( 4 ), inhibited human IRAP and aminopeptidase N (AP‐N) activity with similar potency as angiotensin IV but was considerably more stable than angiotensin IV toward enzymatic degradation. The compound provides a promising starting point for further optimization toward more drug‐like derivatives. The cyclic constrained analogs allowed us to propose a tentative bioactive conformation of angiotensin IV and it seems that the peptide adopts an inverse γ‐turn at the C ‐terminal. Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd.