title: Conformational constraints in angiotensin IV to probe the role of Tyr², Pro⁵ and Phe⁶.
abstract: The aromatic amino acids Tyr and Phe in angiotensin IV (Ang IV) were conformationally constrained by the use of β-Me substituted analogs, or cyclic constrained analogs. None of these modifications was allowed for Tyr¹, while only e-β-MePhe⁶ substitution resulted in an AngIV analog with high IRAP potency and selectivity versus AP-N or the AT₁ receptor. This indicates an important role of the orientation of the Phe⁶ for inducing selectivity. Pro⁵ replacement with 2-aminocyclopentanecarboxylic acid maintained IRAP potency and abolished AT₁ affinity. These results confirm the importance of conformational constrained amino acids to generate selectivity in bioactive peptides.
authors.affiliation: Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.
authors.forename: Aneta
authors.initials: A
authors.lastname: Lukaszuk
authors.forename: Heidi
authors.initials: H
authors.lastname: Demaegdt
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van den Eynde
authors.forename: Patrick
authors.initials: P
authors.lastname: Vanderheyden
authors.forename: Georges
authors.initials: G
authors.lastname: Vauquelin
authors.forename: Dirk
authors.initials: D
authors.lastname: Tourwé
mesh_terms: D000626:Aminopeptidases / Q000378:metabolism; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D011392:Proline / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D013054:Spectrophotometry, Atomic; D013379:Substrate Specificity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; D014443:Tyrosine; D010649:Phenylalanine; D011392:Proline; D000626:Aminopeptidases