Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity

Samer O. Abdul-Hay, Amy L. Lane, Thomas R. Caulfield, Clémence Claussin, Juliette Bertrand, Amandine Masson, Shakeel Choudhry, Abdul H. Fauq, Guhlam M. Maharvi, Malcolm A. Leissring

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that degrades insulin and the amyloid ß-protein and is strongly implicated in the pathogenesis of diabetes and Alzheimer's disease. We recently developed the first effective inhibitors of IDE, peptide hydroxamates that, while highly potent and selective, are relatively large (MW > 740) and difficult to synthesize. We present here a facile synthetic route that yields enantiomerically pure derivatives comparable in potency to the parent compounds. Through the generation of truncated variants, we identified a compound with significantly reduced size (MW = 455.5) that nonetheless retains good potency (ki = 78 ± 11 nM) and selectivity for IDE. Notably, the potency of these inhibitors was found to vary as much as 60-fold in a substrate-specific manner, an unexpected finding for active site-directed inhibitors. Collectively, our findings demonstrate that potent, small-molecule IDE inhibitors can be developed that, in certain instances, can be highly substrate selective.

Original languageEnglish (US)
Pages (from-to)2246-2255
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number6
StatePublished - Mar 28 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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