Beta-amino acid substitution to investigate the recognition of angiotensin II (AngII) by angiotensin converting enzyme 2 (ACE2)

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

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6 Citations (Scopus)


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 beta-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 beta-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 beta-substitution can dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage. beta-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 beta-turn structure and enhanced substrate cleavage. beta-amino acid substitution in the C-terminal region significantly diminished both secondary structure and proteolytic processing by ACE2. The beta-AngII analogs with enhanced or decreased proteolytic stability have potential application for therapeutic intervention in cardiovascular disease.
Original languageEnglish
Pages (from-to)235 - 244
Number of pages10
JournalJournal of Molecular Recognition
Issue number2
Publication statusPublished - 2011

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