Cyclic insulin-regulated aminopeptidase (IRAP)/AT4 receptor ligands.
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.
Axén
Andreas
A
Department of Medicinal Chemistry, Uppsala University, Box 574, SE-75123 Uppsala, Sweden.
Lindeberg
Gunnar
G
Demaegdt
Heidi
H
Vauquelin
Georges
G
Karlén
Anders
A
Hallberg
Mathias
M
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D003553:Cystine / Q000737:chemistry; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship
C090830:AT4 receptor; D004220:Disulfides; D004791:Enzyme Inhibitors; D008024:Ligands; D010456:Peptides, Cyclic; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D003553:Cystine; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase