Identification of an allosteric hotspot for additive activation of PPARγ in antidiabetic effects

可以诱导PPARγ相加效应的变构热区的识别

Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of TZDs is challenging because of their side effects,including weight gain and hepatotoxicity.Here,we found that bavachinin(BVC),a lead natural product,additively activates PPARγ with lowdose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy.Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARy,thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG.Based on this hotspot,we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC.Together,our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists,and the combination thera py of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.

PPARγ激动剂-噻唑烷二酮类药物(thiazolidinedione,TZD)为治疗2型糖尿病的胰岛素增敏剂.尽管TZD药物具有强有效的药理活性,但其日益凸显的毒副作用已经被证实与常规使用剂量成正相关.目前为止,尚无一种有效的方式可以平衡TZD药物的药理活性和毒副作用.本研究发现补骨脂二氢黄酮甲醚(BVC)可以通过触发PPARγ的全新变构位点,来累积放大RSG的抗糖尿病活性,同时缓解其毒副作用的发生.BVC可协同增强TZD对PPARγ转录活性的激动作用,进而相加诱导低剂量RSG的胰岛素增敏性,同时缓解RSG单独用药时造成的体重增加和肝肾毒性副作用.BVC与RSG可同时结合在PPARγY型空腔中,其中BVC占据TZD右上方由螺旋-H3、螺旋H5、β折叠-3以及Loop 7构成的口袋.位于螺旋H5上的Met329和Ser332周围的变构热区介导了BVC触发的相加效应.基于该变构热区,本文筛选了一系列新型的变构激动剂,而且其同时具备与TZD的相加效应.这些工作揭示了选择性变构调控PPARγ的新方向,可望为2型糖尿病的治疗方式提供一种新思路.