核受体FXR选择性募集辅激活因子的结构分子机理及其调控的生理功能

Nuclear receptor FXR is an important drug target. However, the regulation mechanisms by which FXR exerts its therapeutic or side effects are still unclear. Co-regulator recruitment by nuclear receptors is the main pathway for their regulatory functions. Our preliminary research found a natural product, tschimganine, as a novel ligand for FXR. Tschimganine has a novel molecular structure, binds to FXR with a unique binding mode, induces FXR to selectively recruit coactivators, and differentially regulates key target genes different from other FXR ligands. Based on these data, we designed and synthesized a series of tschimganine derivatives. As a result, we got four derivatives that can induce FXR to completely exclude the recruitment of coactivator PGC-1α, while maintain the recruitment ability for other coactivators. In this proposal, we will study the structural mechanism by which FXR selectively recruits different co-activators induced by this kind of novel selective modulators. Combined with the data from microarray assay and the differentially regulated target gene, we will study the consequent signal transduction pathways regulated by the co-activators recruitment of FXR induced by these novel ligands. After that, we will study the physiological and pharmacological functions of these novel ligands using wild-type and FXR gene knock-out mice, and diseases model mice. This research will provide a novel structure template and a drug-design strategy by targeting FXR. Importantly, this research will also provide a useful and clear ligand tool for the research field of FXR, including the signal transduction mechanism and biological functions regulated by FXR.

核受体FXR是当今药物研发的重要靶标。但FXR发挥疗效或产生副作用的分子机理仍不明确。募集辅因子是核受体发挥功能的主要途径，而核受体选择性募集辅因子的配体调控剂已成为核受体靶点药物的研发方向。我们的前期研究发现FXR新配体Tschimganine能调节FXR选择性募集辅激活因子，并存在与现有配体差异调节的关键靶基因。以此为根据，优化合成得到了能使FXR完全不招募PGC-1α而保持与其它辅因子结合的选择性调控剂。本项目将通过结晶学方法研究这类新型化合物诱导FXR选择性募集辅激活因子的结构机理；以差异调节的靶基因为线索，结合芯片分析，研究该选择性产生的下游信号通路；利用野生型、基因敲除型小鼠、疾病模型小鼠研究该选择性产生的生理功能和疾病疗效。这些研究，将为FXR提供一个能选择性招募辅因子的配体工具化合物，为FXR的功能机理研究提供新思路，为以FXR为靶标的药物研发提供新的结构模板和设计方向。

核受体FXR是当今药物研发的重要靶标。但FXR发挥疗效或产生副作用的分子机理仍不明确。募集辅调节因子是核受体发挥功能的主要途径，而选择性募集辅调节因子的配体调控剂已成为核受体靶点药物的研发方向。我们研究发现了FXR一系列新配体能调节FXR选择性募集辅激活因子，并存在与现有配体差异调节的关键靶基因。基于系统的构效关系机理研究此为根据，我们进一步优化合成得到了能使FXR完全不招募PGC-1α而保持其它辅因子结合的选择性调控剂。本项目通过结晶学方法研究这类新型化合物诱导FXR选择性募集辅激活因子的结构机理；以差异调节的靶基因为线索，结合芯片分析，研究FXR选择性募集辅激活因子产生的下游信号通路；利用野生型、基因敲除型小鼠研究了该选择性产生的生理功能和疾病疗效。这些研究，将为FXR提供一个具有明确调控特性的配体工具化合物，为FXR的功能机理提供新思路，为以FXR为靶标的药物研发提供新的结构模板和设计方向。