Abstract：
PPARγ full agonists, thiazolidinediones (TZDs), have been known as a class of most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, recently their therapeutic benefits have been compromised by several undesirable side effects. In this study, a host-based repurposing strategy and in combination with comprehensive biological evaluations were synergistically employed to seek for potent PPARγ ligands, which led to the identification of an anti-thrombotic drug, dicoumarol (Dic), as the novel and safer selectively PPARγ modulator (SPPARγM) with advantages over current TZD drugs. The results in vitro showed that Dic had a potent binding affinity and weakly agonistic activity for PPARγ and its downstream key genes. Moreover, in diabetic model, it significantly reduced blood glucose without leading to the weight gain of both body and main organ tissues. Further mechanistic investigations revealed that Dic possessed such desired pharmacological properties mainly through effectively inhibiting the phosphorylation of PPARγ-Ser273 and selectively regulating the expressions of insulin-sensitive and resistance genes. Finally, the docking studies on the analysis of the potent binding mode of Dic with PPARγ revealed a remarkable difference on interaction region compared with other developed PPARγ agonists, which not only gave a proof of concept for the abovementioned mechanism but also provided the molecular basis for the discrimination of Dic from other PPARγ ligands, especially TZD drugs. Taken together, our findings suggested that Dic could serve as a new and promising candidate with good therapeutic index for treating T2DM, especially for those T2DM patients with thrombosis.
摘要：
PPARγ完全激动剂，噻唑烷二酮（TZDs），被称为治疗2型糖尿病(T2DM)的一类最有效的药物。然而,最近，它们的治疗益处已经被几种不良副作用所损害。在这项研究中,以宿主为基础的再利用策略，并结合全面的生物学评估，协同地寻求有效的PPARγ配体，这导致了抗血栓药物的鉴定，dicoumarol(Dic),作为新型且更安全的选择性PPARγ调节剂（SPPARγM），具有优于现有TZD药物的优势。体外结果表明，Dic对PPARγ及其下游关键基因具有强结合亲和力和弱激动活性。此外，在糖尿病模型中，它显著降低血糖，而不会导致身体和主要器官组织的体重增加。进一步的机理研究表明，Dic主要通过有效抑制PPARγ-Ser273的磷酸化并选择性调节胰岛素敏感和抵抗基因的表达而具有所需的药理特性。最后,对Dic与PPARγ的有效结合模式分析的对接研究显示，与其他已开发的PPARγ激动剂相比，相互作用区域存在显着差异，这不仅证明了上述机制的概念，而且为Dic与其他PPARγ配体的区别提供了分子基础，尤其是TZD药物.一起来看,我们的研究结果表明，Dic可以作为一个新的和有希望的候选人，具有良好的治疗指数的T2DM，尤其是那些有血栓形成的T2DM患者。
