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Nat Chem Biol DOI:10.1038/s41589-019-0271-0

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

Publication TypeJournal Article
Year of Publication2019
AuthorsMaianti, JPablo, Tan, GA, Vetere, A, Welsh, AJ, Wagner, BK, Seeliger, MA, Liu, DR
JournalNat Chem Biol
Date Published2019 May 13

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.


Alternate JournalNat. Chem. Biol.
PubMed ID31086331