Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26

The naturally occurring phosphonotripeptide K-26 is a potent angiotensin converting enzyme (ACE) inhibitor containing an α-amino phosphonic acid analogue of tyrosine. Previous studies have demonstrated that canonical peptide analogues of K-26 are micromolar inhibitors of ACE. To ascertain the structure–activity relationships in this class of ACE inhibitory natural products, K-26 and eight analogues were chemically synthesized and evaluated. Phosphonyl substitution was found to be the critical determinant of activity, resulting in a 1500-fold increase in ACE inhibition versus carboxyl analogues. Secondarily, the absolute configuration of the terminal α-amino phosphonate and N-acetylation were found to significantly modulate ACE inhibitory activity.

Graphical abstractIn order to ascertain the structure–activity relationships in an uninvestigated class of ACE inhibitory natural products, K-26 and eight analogues were chemically synthesized and evaluated.Figure optionsDownload full-size imageDownload as PowerPoint slide