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Publication Abstract from PubMed

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.

Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme.,Maianti JP, Tan GA, Vetere A, Welsh AJ, Wagner BK, Seeliger MA, Liu DR Nat Chem Biol. 2019 Jun;15(6):565-574. doi: 10.1038/s41589-019-0271-0. Epub 2019 , May 13. PMID:31086331^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.