deCODE biostructures, Bainbridge Island, Washington, USA.
Nat Biotechnol. 2010 Jan;28(1):63-70. doi: 10.1038/nbt.1598. Epub 2009 Dec 27.
Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.
磷酸二酯酶 4（PDE4）是细胞中主要的 cAMP 水解酶，是广泛疾病的有前途的药物靶点。在这里，我们展示了 PDE4 和结合抑制剂的七个共晶结构，这些结构显示调节域封闭在活性部位上，从而揭示了 PDE4 调节的结构基础。这种结构上的见解，加上支持的突变和动力学研究，使我们能够设计 PDE4D 的小分子别构调节剂，这些调节剂不完全抑制酶活性（I（max）约为 80-90％）。这些别构调节剂具有降低引起呕吐的潜力，呕吐是现有活性位点定向 PDE4 抑制剂的剂量限制副作用，同时在细胞和体内模型中保持生物活性。我们的结果可能有助于设计调节 cAMP 信号传导的 CNS 治疗药物，用于治疗阿尔茨海默病、亨廷顿病、精神分裂症和抑郁症，其中需要治疗益处的脑分布。
