Interkingdom Pharmacology of Angiotensin‑I Converting Enzyme Inhibitor Phosphonates Produced by Actinomycetes

The K-26 family of bacterial secondary metabolites are N-modified tripeptides terminated by an unusual phosphonate analog of tyrosine. These natural products, produced via three different actinomycetales, are potent inhibitors of human angiotensin-I converting enzyme (ACE). Herein we investigate the...

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Published in:ACS medicinal chemistry letters 2014-04, Vol.5 (4), p.346-351
Main Authors: Kramer, Glenna J, Mohd, Akif, Schwager, Sylva L. U, Masuyer, Geoffrey, Acharya, K. Ravi, Sturrock, Edward D, Bachmann, Brian O
Format: Article
Language:English
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Letter
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Summary:The K-26 family of bacterial secondary metabolites are N-modified tripeptides terminated by an unusual phosphonate analog of tyrosine. These natural products, produced via three different actinomycetales, are potent inhibitors of human angiotensin-I converting enzyme (ACE). Herein we investigate the interkingdom pharmacology of the K-26 family by synthesizing these metabolites and assessing their potency as inhibitors of both the N-terminal and C-terminal domains of human ACE. In most cases, selectivity for the C-terminal domain of ACE is displayed. Co-crystallization of K-26 in both domains of human ACE reveals the structural basis of the potent inhibition and has shown an unusual binding motif that may guide future design of domain-selective inhibitors. Finally, the activity of K-26 is assayed against a cohort of microbially produced ACE relatives. In contrast to the synthetic ACE inhibitor captopril, which demonstrates broad interkingdom inhibition of ACE-like enzymes, K-26 selectively targets the eukaryotic family.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml4004588