Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26

Ioanna Ntai, Brian O. Bachmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3068-3071
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number10
DOIs
StatePublished - May 15 2008

Keywords

  • ACE
  • Angiotensin
  • Inhibitor
  • K-26
  • Natural product
  • Phosphonate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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