You are here

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
ISSN1552-4469
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.

DOI10.1038/s41589-019-0271-0
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/31086331?dopt=Abstract

Alternate JournalNat. Chem. Biol.
PubMed ID31086331