TY - JOUR
T1 - Optimization of peptide hydroxamate inhibitors of insulin-degrading enzyme reveals marked substrate-selectivity
AU - Abdul-Hay, Samer O.
AU - Lane, Amy L.
AU - Caulfield, Thomas R.
AU - Claussin, Clémence
AU - Bertrand, Juliette
AU - Masson, Amandine
AU - Choudhry, Shakeel
AU - Fauq, Abdul H.
AU - Maharvi, Guhlam M.
AU - Leissring, Malcolm A.
PY - 2013/3/28
Y1 - 2013/3/28
N2 - 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.
AB - 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.
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U2 - 10.1021/jm301280p
DO - 10.1021/jm301280p
M3 - Article
C2 - 23437776
AN - SCOPUS:84875750447
SN - 0022-2623
VL - 56
SP - 2246
EP - 2255
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -