A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects
A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects
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DOI：
10.1074/jbc.m401552200
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发表时间：
2004-09-24
影响因子：
4.8
通讯作者：
Jendeberg, L
中科院分区：
文献类型：
--
作者：
Östberg, T;Svensson, S;Jendeberg, L
过氧化物酶体增殖物激活受体（PPARs）是核受体NR 1亚家族的配体激活的转录因子。PPARs在控制葡萄糖和脂质稳态中起关键作用，并且合成的异构体特异性PPARs激动剂在临床上用于改善胰岛素敏感性和降低血清甘油三酯水平。所有先前报道的PPAR激动剂与受体形成相同的特征性相互作用，这被认为对诱导激动活性很重要。在这里，我们描述了一类新的PPARalpha/gamma调节剂，5-取代的2-苯甲酰基氨基苯甲酸（2-BABA）。如X射线晶体学所示，代表性化合物BVT. 13、BVT. 762和BVT. 763利用新的结合表位并且缺乏激动剂特征性相互作用。尽管如此，2-BABA家族中的一些化合物在基于细胞的报告基因测定中是有效的激动剂。此外，BVT. 13在ob/ob小鼠中显示出抗糖尿病作用。我们的结论是，2-BABA结合模式可用于设计异构体特异性的PPAR调节剂的生物活性在体内。
The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPARalpha/gamma modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.