During islet transplantation, mitogen-activated protein kinase (MAPK) p38 is preferentially activated in response to the isolation of islets and the associated inflammation. Although therapeutic effects of p38 inhibitors are expected, the clinical application of small-molecule inhibitors of p38 is not recommended because of their serious adverse effects on the liver and central nervous system. Here we designed peptides to inhibit p38, which were derived from the sites on p38 that mediate binding to proteins such as MAPK kinases. Peptide 11R-p38I110 significantly inhibited the activation of p38. To evaluate the effects of 11R-p38I110 , porcine islets were incubated with 10 µmol/L 11R-p38I110 or a mutant form designated 11R-mp38I110 . After islet transplantation, blood glucose levels reached the normoglycemic range in 58.3% and 0% of diabetic mice treated with 11R-p38I110 or 11R-mp38I110 , respectively. These data suggest that 11R-p38I110 inhibited islet apoptosis and improved islet function. Peptide p38I110 is a noncompetitive inhibitor of ATP and targets a unique docking site. Therefore, 11R-p38I110 specifically inhibits p38 activation, which may avoid the adverse effects that have discouraged the clinical use of small-molecule inhibitors of p38. Moreover, our methodology to design "peptide inhibitors" could be used to design other inhibitors derived from the binding sites of proteins.

中文翻译：

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新型细胞渗透性 p38-MAPK 抑制剂可有效防止猪胰岛细胞凋亡并改善胰岛移植物功能。

在胰岛移植过程中，有丝分裂原活化蛋白激酶 (MAPK) p38 优先被激活以响应胰岛的分离和相关的炎症。虽然p38抑制剂的治疗效果是预期的，但由于p38小分子抑制剂对肝脏和中枢神经系统的不良反应严重，不推荐临床应用。在这里，我们设计了抑制 p38 的肽，这些肽来源于 p38 上介导与蛋白质（如 MAPK 激酶）结合的位点。肽 11R-p38I110 显着抑制 p38 的激活。为了评估 11R-p38I110 的作用，将猪胰岛与 10 µmol/L 11R-p38I110 或指定为 11R-mp38I110 的突变体一起孵育。胰岛移植后，血糖水平在 58 岁时达到正常血糖范围。分别有 3% 和 0% 的糖尿病小鼠接受 11R-p38I110 或 11R-mp38I110 治疗。这些数据表明 11R-p38I110 抑制胰岛细胞凋亡并改善胰岛功能。肽 p38I110 是 ATP 的非竞争性抑制剂，靶向一个独特的停靠位点。因此，11R-p38I110 特异性抑制 p38 激活，这可能避免阻碍 p38 小分子抑制剂临床使用的不良反应。此外，我们设计“肽抑制剂”的方法可用于设计源自蛋白质结合位点的其他抑制剂。11R-p38I110 特异性抑制 p38 激活，这可以避免阻碍 p38 小分子抑制剂临床使用的不良反应。此外，我们设计“肽抑制剂”的方法可用于设计源自蛋白质结合位点的其他抑制剂。11R-p38I110 特异性抑制 p38 激活，这可以避免阻碍 p38 小分子抑制剂临床使用的不良反应。此外，我们设计“肽抑制剂”的方法可用于设计源自蛋白质结合位点的其他抑制剂。