Potent Inhibitor of Insulin Degrading Enzyme Reported

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Ii1 structure
Ii1
A new study from a Mayo Clinic-led research team has identified novel, potent inhibitors of insulin degrading enzyme (IDE). Despite an interest in IDE for over 50 years, because of its involvement in insulin catabolism, these are the first potent and selective inhibitors of the enzyme to be described. Given their peptidic nature the current compounds are unlikely to be drugs themselves, but the team hope that their findings will enable further exploration of IDE inhibition as a therapy for diabetes.

IDE is a ubiquitously expressed, secreted enzyme belonging to a small superfamily of zinc-metalloproteases that evolved independently of conventional zinc-metalloproteases. This difference is emphasised by the team’s finding that potent, non-selective hydroxamate inhibitors of zinc metalloproteases did not inhibit IDE.

Crystal structure of the Ii1-IDE complex (PDB ID 3E4A)
Crystal structure of the Ii1-IDE complex (PDB ID 3E4A)
A high-throughput screening campaign failed to identify useful hits, so the researchers turned to a substrate-based approach leading to identification of Ii1 (Inhibitor of IDE 1), with a Ki of 1.7nM. Additional biostructural work identified the distinctive mechanism of IDE inhibition.

In vitro studies with the inhibitors, which included equipotent retro-inverso peptide analogues, demonstrated potent inhibition of extracellular insulin catabolism. In addition, and somewhat unexpectedly, IDE inhibition also enhanced insulin signalling, suggesting IDE involvement in intracellular degradation of insulin.

As well as cleaving insulin, IDE degrades a number of other substrates including atrial natriuretic peptide, glucagon and amyloid-β protein (Aβ). Indeed there has been considerable interest in up-regulating IDE activity as a potential therapy for Alzheimer’s disease (AD). The authors of the current study, published in PLoS ONE, suggest that any concern regarding negative impacts of IDE inhibition on AD could be addressed by developing inhibitors that do not cross the blood-brain barrier. Further, in light of the recent finding that intranasal insulin improves cognition in early AD patients, and given insulin’s beneficial effects on learning and memory, it may be overly simplistic to assume that IDE’s role in AD pathogenesis is limited to its predicted effects on Aβ alone.

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