Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme

Juan Pablo Maianti, Grace A. Tan, Amedeo Vetere, Amie J. Welsh, Bridget K. Wagner, Markus A. Seeliger, David R. Liu

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Enzymes that act on multiple substrates are common in biology but pose unique challenges as therapeutic targets. The metalloprotease insulin-degrading enzyme (IDE) modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. However, IDE also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin. IDE inhibitors to treat diabetes, therefore, should prevent IDE-mediated insulin degradation, but not glucagon degradation, in contrast with traditional modes of enzyme inhibition. Using a high-throughput screen for non-active-site ligands, we discovered potent and highly specific small-molecule inhibitors that alter IDE’s substrate selectivity. X-ray co-crystal structures, including an IDE-ligand-glucagon ternary complex, revealed substrate-dependent interactions that enable these inhibitors to potently block insulin binding while allowing glucagon cleavage, even at saturating inhibitor concentrations. These findings suggest a path for developing IDE-targeting therapeutics, and offer a blueprint for modulating other enzymes in a substrate-selective manner to unlock their therapeutic potential.

Original languageEnglish (US)
Pages (from-to)565-574
Number of pages10
JournalNature Chemical Biology
Volume15
Issue number6
DOIs
StatePublished - Jun 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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