Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
复制标题
小分子对胰岛素降解酶的催化位点诱导小鼠葡萄糖不耐症。
DOI：
10.1038/ncomms9250
复制
发表时间：
2015-09-23
影响因子：
16.6
通讯作者：
Deprez B
中科院分区：
文献类型：
--
作者：
Deprez-Poulain R;Hennuyer N;Bosc D;Liang WG;Enée E;Marechal X;Charton J;Totobenazara J;Berte G;Jahklal J;Verdelet T;Dumont J;Dassonneville S;Woitrain E;Gauriot M;Paquet C;Duplan I;Hermant P;Cantrelle FX;Sevin E;Culot M;Landry V;Herledan A;Piveteau C;Lippens G;Leroux F;Tang WJ;van Endert P;Staels B;Deprez B
胰岛素降解酶（insulin-degradingenzyme，IDE）是一种能降解胰岛素和β淀粉样蛋白等生物活性肽的蛋白酶。基因敲除和遗传研究已经将IDE与阿尔茨海默病和2型糖尿病联系起来。IDE作为主要的胰岛素降解蛋白酶，是治疗糖尿病的候选药物靶点。在这里，我们使用动力学靶向合成来设计第一个适合于体内研究的IDE催化位点抑制剂（BDM 44768）。晶体学和小角X射线散射分析表明，它锁定IDE在一个封闭的构象。在一组金属蛋白酶中，BDM 44768选择性地抑制IDE。用BDM 44768对小鼠进行急性治疗增加了胰岛素信号传导，并令人惊讶地以IDE依赖性方式损害了葡萄糖耐量。这些结果证实IDE参与调节短期葡萄糖稳态的途径，但对抑制IDE催化活性治疗糖尿病的一般有效性表示怀疑。 抑制胰岛素降解酶（IDE）已被提出作为治疗糖尿病患者的潜在治疗策略。在这里，作者开发了一种新型IDE抑制剂，但令人惊讶的是，IDE抑制对小鼠的葡萄糖耐量有负面影响。
Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes. Inhibiting insulin-degrading enzyme (IDE) has been proposed as a potential therapeutic strategy for the treatment of patients with diabetes. Here, the authors develop a novel IDE inhibitor but find that, surprisingly, IDE inhibition has negative effects on glucose tolerance in mice.