Insulin-degrading enzyme (IDE) is a thiol-sensitive zinc-metallopeptidase that acts as the major insulin-degrading protease in vivo, mediating the termination of insulin signaling. In addition to regulating insulin action in diabetes pathogenesis, IDE plays a role in Varicella-Zoster virus infection and degradation of amyloid-β, a peptide implicated in Alzheimer’s disease. ML-345 is a small molecule inhibitor that selectively targets cysteine819 in IDE with an EC50 value of 188 nM. It demonstrates 10-fold selectivity for IDE over a panel of enzymes with reactive cysteine residues.
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