Frkic Rebecca L, Chua Benjamin S, Shin Youseung, Pascal Bruce D, Novick Scott J, Kamenecka Theodore M, Griffin Patrick R, Bruning John B
Institute for Photonics and Advanced Sensing (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5005, Australia.
Department of Molecular Medicine, The Scripps Research Institute, Jupiter, Florida 33458, United States.
Nucl Receptor Res. 2018;5. doi: 10.11131/2018/101350.
Targeting peroxisome proliferator-activated receptor (PPAR) by synthetic compounds has been shown to elicit insulin sensitising properties in type 2 diabetics. Treatment with a class of these compounds, the thiazolidinediones (TZDs), has shown adverse side effects such as weight gain, fluid retention, and congestive heart failure. This is due to their full agonist properties on the receptor, where a number of genes are upregulated beyond normal physiological levels. Lessened transactivation of PPAR by partial agonists has proved beneficial in terms of reducing side effects, while still maintaining insulin sensitising properties. However, some partial agonists have been associated with unfavourable pharmacokinetic profiles due to their acidic moieties, often causing partitioning to the liver. Here we present SR1988, a new partial agonist with favourable non-acid chemical properties. We used a combination of X-ray crystallography and hydrogen/deuterium exchange (HDX) to elucidate the structural basis for reduced activation of PPAR by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.
合成化合物靶向过氧化物酶体增殖物激活受体（PPAR）已被证明可在2型糖尿病患者中引发胰岛素增敏特性。使用一类这样的化合物，即噻唑烷二酮类（TZDs）进行治疗，已显示出不良副作用，如体重增加、液体潴留和充血性心力衰竭。这是由于它们对该受体具有完全激动剂特性，导致许多基因上调至超出正常生理水平。部分激动剂对PPAR的反式激活作用减弱已被证明在减少副作用方面是有益的，同时仍能保持胰岛素增敏特性。然而，一些部分激动剂由于其酸性基团而具有不良的药代动力学特征，常常导致在肝脏中的分配。在此我们介绍SR1988，一种具有良好非酸性化学性质的新型部分激动剂。我们结合使用X射线晶体学和氢/氘交换（HDX）来阐明SR1988降低PPAR激活的结构基础。这种结构分析揭示了一种通过配体降低AF2共激活剂结合表面稳定性的机制。
