1.
Axén, Andreas, et al.
(författare)
Cyclic insulin-regulated aminopeptidase (IRAP)/AT(4) receptor ligands
2006
Ingår i: Journal of Peptide Science. - : Wiley. - 1075-2617 .- 1099-1387. ; 12:11, s. 705-713
Tidskriftsartikel (refereegranskat) abstract
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.
2.
Georgsson, Jennie, et al.
(författare)
Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
2006
Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 14:17, s. 5963-5972
Tidskriftsartikel (refereegranskat) abstract
Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.
3.
Rosenström, Ulrika, et al.
(författare)
Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT(1) and AT(2) receptors
2006
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:20, s. 6133-6137
Tidskriftsartikel (refereegranskat) abstract
A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT(2) receptor, and one also displayed high affinity for the AT(1) receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT(2) receptor ligands.
