医薬品化学領域における生体超分子集合体の高次微細構造と機能に関する研究

在本项目中，我们对生物超分子组装体的结构和功能进行了详细的研究，如下图(1)-(5)所示。(1)结合研究发现，低密度脂蛋白(LDL)的氧化增强了低密度脂蛋白(LDL)的药物结合亲和力，而低密度脂蛋白氧化导致的负净电荷增加对这种结合增强有显著影响。研究还发现，AGP的主要遗传变异体表现出不同的药物结合性质，其药物结合亲和力和对映体选择性强烈依赖于样品溶液的pH条件。(2)两亲性表面拓扑结构影响血浆载脂蛋白A-1和载脂蛋白E在脂粒表面的相互作用和活化。我们检测了前列腺素和阿片受体…的部分多肽的GI活性更多的是分子相互作用。所有多肽均与Gi形成稳定的络合物，并进一步激活G蛋白。通过核磁共振结构分析，发现N-末端有螺旋结构，药剂形成正电荷团，激活G蛋白。(4)研究了小肽对A-β(阿尔茨海默病)、α-突触核蛋白/NAc(帕金森病)、PrP(PrP)等淀粉样蛋白的二级结构的影响。结果表明，Aβ(1-28)中的Ac-ELVFFAKK-NH_2、NAc(19-35)中的Ac-Etvk-NH2和Ac-KTVE-NH2、PrP(129-154)中的Ac-EFGNK-NH2和Ac-EYYEK-NH2与多肽发生特异性作用。用Monte-Calro模拟方法研究了DPPC双分子膜的统计性质以及维生素E与DPPC平面膜在液晶相中的相互作用。较少

In this project, we performed several researches about the highly detailed structure and the function on a bio-supermolecular assembly which are shown in lower (1) - (5).(1) The binding study using high-performance frontal analysis found that the oxidation of low-density lipoprotein (LDL) enhances the drug binding affinity of LDL, and the increase in negative net charge due to LDL oxidation gives significant effect upon this binding enhancement. It was also found that the major genetic variants of AGP show different drug binding property, and their drug binding affinity and the enantioselectivity strongly depend upon the pH condition of sample solution.(2) Interaction and activation of plasma apolipoproteins A-1 and E at lipid particle surface were influenced by the amphipathic surface topology. Not only surface but core lipid composition of particles played roles in the topology-formation.(3) We examined the Gi activity of partial peptides of a Prostaglandin and an Opioid receptors, a … More nd the molecular interactions. All peptides formed the stable complex with Gi and activated G protein further. As a result of NMR structural analysis, the helix structure is found on the N-terminal.The potion forms a positive charge cluster and is thought that it activates G protein.(4) The effects of small peptides on the secondary structures of the peptides dissected from such amyloidgenic proteins as Aβ(Alzheimer's sisease), α-synuclein/NAC (Parkinson's disease), and PrP (prion disease) were studied. It was found that Ac-ELVFFAKK-NH_2 in Aβ(1-28), Ac-ETVK-NH_2 and Ac-KTVE-NH_2 in NAC(19-35), and Ac-EFGNK-NH_2 in and Ac-EYYEK-NH_2 in PrP(129-154) interact specifically with the peptides. Each of these small peptides could be a lead compound for designing a therapeutic agent for the diseases.(5) The statistical properties of the curved bilayer membranes of DPPC and the interactions of vitamin E with the planar membranes of DPPC in the liquid-crystal phase were studied by Monte-Calro simulation. Less