title: Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity.
abstract: 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.
authors: Department of Neuroscience, Mayo Clinic , Jacksonville, Florida 32224, USA.
authors: Samer O
authors: SO
authors: Abdul-Hay
authors: Amy L
authors: AL
authors: Lane
authors: Thomas R
authors: TR
authors: Caulfield
authors: Clémence
authors: C
authors: Claussin
authors: Juliette
authors: J
authors: Bertrand
authors: Amandine
authors: A
authors: Masson
authors: Shakeel
authors: S
authors: Choudhry
authors: Abdul H
authors: AH
authors: Fauq
authors: Guhlam M
authors: GM
authors: Maharvi
authors: Malcolm A
authors: MA
authors: Leissring
mesh_terms: D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007339:Insulysin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D010455:Peptides; D007339:Insulysin