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 alpha-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 alpha-amino phosphonate and N-acetylation were found to significantly modulate ACE inhibitory activity.
Ntai
Ioanna
I
Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
Bachmann
Brian O
BO
D000192:Actinomycetales / Q000737:chemistry; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D063065:Organophosphonates / Q000737:chemistry; D013329:Structure-Activity Relationship
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D063065:Organophosphonates; C508953:tripeptide K-26