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Cyclic insulin-regulated aminopeptidase (IRAP)/AT4 receptor ligands.
Authors:Andreas Axén  Gunnar Lindeberg  Heidi Demaegdt  Georges Vauquelin  Anders Karlén  Mathias Hallberg
Institution:Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
Abstract:The angiotensin IV receptor (AT4 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.
Keywords:angiotensin IV  insulin‐regulated aminopeptidase  IRAP  cystinyl aminopeptidase  aminopeptidase N  disulfide cyclization  structure–activity relationship  peptide synthesis  bioactive conformation
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