Cyclic insulin-regulated aminopeptidase (IRAP)/AT4 receptor ligands

被引:37
作者
Axen, Andreas
Lindeberg, Gunnar
Demaegdt, Heidi
Vauquelin, Georges
Karlen, Anders
Hallberg, Mathias
机构
[1] Uppsala Univ, Div Biol Res Drug Dependence, Dept Pharmaceut Biosci, SE-75124 Uppsala, Sweden
[2] Uppsala Univ, Dept Med Chem, SE-75123 Uppsala, Sweden
[3] Vrije Univ Brussels, Dept Mol & Biochem Pharmacol, B-1050 Brussels, Belgium
关键词
angiotensin IV; insulin-regulated aminopeptidase; IRAP; cystinyl aminopeptidase; aminopeptidase N; disulfide cyclization; structure -activity relationship; peptide synthesis; bioactive conformation;
D O I
10.1002/psc.782
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 AT4 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/AT4 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 gamma-turn at the C-terminal. Copyright (c) 2006 European Peptide Society and John Wiley & Sons, Ltd.
引用
收藏
页码:705 / 713
页数:9
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