Optimization of Peptide Hydroxamate Inhibitors of Insulin-Degrading Enzyme Reveals Marked Substrate-Selectivity
Optimization of Peptide Hydroxamate Inhibitors of Insulin-Degrading Enzyme Reveals Marked Substrate-Selectivity
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DOI：
10.1021/jm301280p
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发表时间：
2013-03-28
影响因子：
7.3
通讯作者：
Leissring, Malcolm A.
中科院分区：
文献类型：
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作者：
Abdul-Hay, Samer O.;Lane, Amy L.;Leissring, Malcolm A.
胰岛素降解酶（IDE）是一种非典型锌金属肽酶，可降解胰岛素和淀粉样β蛋白，与糖尿病和阿尔茨海默病的发病机制密切相关。我们最近开发了第一个有效的IDE抑制剂，肽异羟肟酸盐，虽然非常有效和选择性，但相对较大（MW > 740）并且难以合成。我们在这里提出了一个简单的合成路线，产生对映体纯的衍生物的效力与母体化合物。通过产生截短的变体，我们鉴定了具有显著减小的尺寸（MW = 455.5）的化合物，其仍然保留了良好的效力（k（i）= 78 +/- 11 nM）和对IDE的选择性。值得注意的是，发现这些抑制剂的效力以底物特异性方式变化多达60倍，这是活性位点定向抑制剂的意外发现。总的来说，我们的研究结果表明，可以开发有效的小分子IDE抑制剂，在某些情况下，可以具有高度底物选择性。
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 (k(i), = 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.