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 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.