β-amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2) Academic Article uri icon

abstract

  • In spite of the important role of angiotensin converting enzyme 2 (ACE2) in the cardiovascular system, little is known about the substrate structural requirements of the AngII-ACE2 interaction. Here we investigate how changes in angiotensin II (AngII) structure affect binding and cleavage by ACE2. A series of C3 β-amino acid AngII analogs were generated and their secondary structure, ACE2 inhibition, and proteolytic stability assessed by circular dichroism (CD), quenched fluorescence substrate (QFS) assay, and LC-MS analysis, respectively. The β-amino acid-substituted AngII analogs showed differences in secondary structure, ACE2 binding and proteolytic stability. In particular, three different subsets of structure-activity profiles were observed corresponding to substitutions in the N-terminus, the central region and the C-terminal region of AngII. The results show that β-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. β-amino acid substitution in the N-terminal region of AngII caused little change in structure or substrate cleavage, while substitution in the central region of AngII lead to increased β-turn structure and enhanced substrate cleavage. β-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The β-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.

authors

  • Clayton, Daniel
  • Hanchapola, Iresha
  • Hausler, Nicholas
  • Unabia, Sharon
  • Lew, Rebecca A
  • Widdop, Robert E
  • Smith, Alexander I
  • Perlmutter, Patrick
  • Aguilar, Marie-Isabel

publication date

  • March 2011