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Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26.

ABSTRACT: 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.

SUBMITTER: Ntai I

PROVIDER: S-EPMC2430421 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Identification of ACE pharmacophore in the phosphonopeptide metabolite K-26.

Ntai Ioanna I Bachmann Brian O BO

Bioorganic & medicinal chemistry letters 20071205 10

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 critica ...[more]

PMID: 18096385

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