1. Conformational constraints in angiotensin IV to probe the role of Tyr2, Pro5 and Phe6
- Author
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Isabelle Van den Eynde, Patrick Vanderheyden, Georges Vauquelin, Heidi Demaegdt, Aneta Lukaszuk, and Dirk Tourwé
- Subjects
Pharmacology ,chemistry.chemical_classification ,biology ,Stereochemistry ,Organic Chemistry ,Phenylalanine ,General Medicine ,biology.organism_classification ,Biochemistry ,Angiotensin II ,Amino acid ,chemistry.chemical_compound ,Protein structure ,chemistry ,Structural Biology ,Drug Discovery ,Aromatic amino acids ,Molecular Medicine ,Cricetulus ,Tyrosine ,Selectivity ,Molecular Biology - 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.
- Published
- 2011