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首页> 外文期刊>Journal of Molecular Biology >INT131: A Selective Modulator of PPARgamma
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INT131: A Selective Modulator of PPARgamma

机译：INT131：PPARgamma的选择性调制器

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The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR7; NR1C3) plays a central role in adipogenesis and is the molecular target of the thiazolidinedione class of antidiabetic drugs. To overcome the well-known shortcomings of thiazolidinediones, we have identified INT131 (formerly T131 and AMG131) as a potent selective ligand for PPARgamma that is structurally and pharmacologically distinct from glitazone agonists. In vitro biochemical and cell-based functional assays showed that INT131 mediates a distinct pattern of coregulator recruitment to PPARgamma. In adipocytes, INT131 showed minimal stimulation of adipocyte differentiation and partially activated PPARgamma target genes involved in adipogenesis and, at the same time, showed more agonistic activity on another set of target genes that may influence insulin sensitivity directly. These unique properties of INT131 may provide a mechanistic basis for its distinct pharmacological profile. In vivo, increases in glucose tolerance were observed in Zucker (fa/fa) rats following a 14-day oral treatment with INT131. Although the maximal efficacies of INT131 and rosiglitazone were similar with respect to improvements in glucose tolerance, INT131 had less effect on heart and lung weights, weight gain, hemodilution, and plasma volume. Thus, INT131 appears to selectively modulate PPARgamma responses in an in vivo preclinical model, showing antidiabetic efficacy while exhibiting an improved hemo-dynamic and cardiovascular adverse effect profile compared to the full agonist rosiglitazone. X-ray crystallography revealed that INT131 interacts with PPARgamma through a distinct binding mode, forming primarily hydro-phobic contacts with the ligand-binding pocket without direct hydrogen-bonding interactions to key residues in helix 12 that are characteristic of full agonists. Mutagenesis studies on Tyr473 in helix 12 demonstrated this residue as essential for rosiglitazone-induced receptor activation, but non-essential for INT131 function in vitro, providing one possible molecular determinant for INT131's distinct pharmacology. INT131 is currently being evaluated in a clinical setting as a therapeutic agent for the treatment of type 2 diabetes#
机译：核激素受体过氧化物酶体增殖物激活的受体γ（PPAR7; NR1C3）在脂肪形成中起着核心作用，是噻唑烷二酮类抗糖尿病药物的分子靶标。为克服噻唑烷二酮类的众所周知的缺点，我们将INT131（以前称为T131和AMG131）鉴定为PPARgamma的有效选择性配体，该配体在结构和药理学上与格列酮激动剂不同。体外生化和基于细胞的功能分析表明，INT131介导了共调节剂募集到PPARgamma的独特模式。在脂肪细胞中，INT131对脂肪细胞分化的刺激最小，并且参与脂肪形成的PPARgamma目标基因被部分激活，同时，对另一组可能直接影响胰岛素敏感性的目标基因表现出更多的激动作用。 INT131的这些独特特性可为其独特的药理特性提供机理基础。在体内，用INT131口服治疗14天后，在Zucker（fa / fa）大鼠中观察到了葡萄糖耐量的增加。尽管就改善糖耐量而言，INT131和罗格列酮的最大功效相似，但INT131对心脏和肺部重量，体重增加，血液稀释和血浆容量的影响较小。因此，与完全激动剂罗格列酮相比，INT131似乎在体内临床前模型中选择性调节PPARγ反应，显示出抗糖尿病功效，同时表现出改善的血液动力学和心血管不良反应。 X射线晶体学表明INT131通过独特的结合模式与PPARγ相互作用，主要与配体结合袋形成疏水接触，而没有与完整激动剂特征的螺旋12中的关键残基直接发生氢键相互作用。螺旋12中Tyr473的诱变研究表明，该残基是罗格列酮诱导的受体激活所必需的，但对于INT131的体外功能却不是必需的，为INT131的独特药理作用提供了一种可能的分子决定因素。 INT131目前正在临床中评估为2型糖尿病的治疗剂＃

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