The replacement of His(4) in angiotensin IV by conformationally constrained residues provides highly potent and selective analogues

Aneta Lukaszuk; Heidi Demaegdt; Debby Feytens; Patrick Vanderheyden; Georges Vauquelin; Dirk Tourwé

doi:10.1021/jm900651p

The replacement of His(4) in angiotensin IV by conformationally constrained residues provides highly potent and selective analogues

J Med Chem. 2009 Sep 24;52(18):5612-8. doi: 10.1021/jm900651p.

Authors

Aneta Lukaszuk¹, Heidi Demaegdt, Debby Feytens, Patrick Vanderheyden, Georges Vauquelin, Dirk Tourwé

Affiliation

¹ Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium.

PMID: 19757839
DOI: 10.1021/jm900651p

Abstract

The histidine residue in angiotensin IV was replaced by various conformationally constrained amino acids. The substitution of the His(4)-Pro(5) dipeptide sequence by the constrained Trp analogue Aia-Gly, in combination with beta(2)hVal substitution at the N-terminus, provided a new stable analogue H-(R)-beta(2)hVal-Tyr-Ile-Aia-Gly-Phe-OH (AL-40) that is a potent ligand for the Ang IV receptor IRAP and selective versus AP-N and the AT1 receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Aminopeptidases / metabolism
Angiotensin II / analogs & derivatives*
Angiotensin II / chemistry
Angiotensin II / metabolism
Animals
Azepines / chemistry
Biomimetics
CHO Cells
Carboxylic Acids / chemistry
Cricetinae
Cricetulus
Cystinyl Aminopeptidase / metabolism
Histidine*
Humans
Phenylalanine / chemistry
Protein Conformation
Receptor, Angiotensin, Type 1 / metabolism
Substrate Specificity

Substances

Azepines
Carboxylic Acids
Receptor, Angiotensin, Type 1
Angiotensin II
angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-
Phenylalanine
Histidine
Aminopeptidases
Cystinyl Aminopeptidase
leucyl-cystinyl aminopeptidase