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

生物超分子组装体高阶精细结构与功能在药物化学领域的研究

• 批准号: 12470489
• 负责人: TAGA Tooru
• 金额: $ 9.6万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470489/
• 关键词: SPR; Biosuper molecular Assembly; Highly fine structure; high performance fromtall Analysis; low density lipo-protein; apo A-1; any loid; Monte Carlo-cal; 表面ブラズモン共鳴; apoA-1; 表面プラスモン共鳴; 低密度血漿リポタンパク質; 脂質2分子層; 血漿アポリポタンパク質; レセプター; アルツハイマー; シミュ

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

在这个项目中，我们对生物超分子组装体的高度详细的结构和功能进行了多项研究，如下图（1）-（5）所示。（1）使用高性能前沿分析的结合研究发现，低密度脂蛋白（LDL）的氧化增强了LDL的药物结合亲和力，并且LDL氧化导致的负净电荷的增加对该结合产生了显着影响。 增强。研究还发现AGP的主要遗传变异表现出不同的药物结合特性，其药物结合亲和力和对映选择性强烈依赖于样品溶液的pH条件。(2)血浆载脂蛋白A-1和E在脂质颗粒表面的相互作用和活化受到两亲性表面拓扑的影响。不仅颗粒的表面而且核心脂质成分在拓扑形成中发挥作用。(3) 我们检查了前列腺素和阿片受体的部分肽的 Gi 活性、以及分子相互作用。所有肽均与Gi形成稳定的复合物并进一步激活G蛋白。 NMR结构分析的结果，在N末端发现了螺旋结构。该药剂形成正电荷簇，被认为激活G蛋白。(4)小肽对从Aβ(阿尔茨海默病)、α-突触核蛋白/NAC(帕金森病)和PrP等淀粉样蛋白中分离出的肽的二级结构的影响 （朊病毒病）进行了研究。发现Aβ(1-28)中的Ac-ELVFFAKK-NH_2、NAC(19-35)中的Ac-ETVK-NH_2和Ac-KTVE-NH_2以及PrP(129-154)中的Ac-EFGNK-NH_2和Ac-EYYEK-NH_2与肽发生特异性相互作用。这些小肽中的每一个都可以成为设计疾病治疗药物的先导化合物。(5)通过Monte-Calro模拟研究了DPPC弯曲双层膜的统计特性以及液晶相中维生素E与DPPC平面膜的相互作用。较少的

项目成果

Kazuhide Miyamoto et al.: "Solution structure of the inactivation gate particle peptides of rat brain type-II A and human heart sodium channels in SDS micelles"J. Peptide Res.. 57. 203-214 (2001)

Kazuhide Miyamoto等：“SDS胶束中大鼠脑II A型和人心脏钠通道失活门颗粒肽的溶液结构”J.

Yoshihiro Kuroda et al.: "Oligopeptide-mediated stabilization of the alpha-helix of a prion Protein peptide"J. A. C. S.. 122. 12596-12597 (2000)

Yoshihiro Kuroda 等人：“寡肽介导的朊病毒蛋白肽 α 螺旋的稳定化”J.

Hiroyuki Saito dt al.: "Interactions of Phosphatidyl choline Surface Monoloybrs. With Triglyceride Cone and Enlianced Apo. A-1 Bindeng in Lipid Emulsions"Langmuin. 17. 2528-2532 (2001)

Hiroyuki Saito dt al.：“磷脂酰胆碱表面单体与甘油三酯锥体和强化 Apo 的相互作用。脂质乳液中的 A-1 Bindeng”Langmuin。

Yoshihiro Kuroda: "Oligopeptide-mediated stabilization of the alpha-helix of prion Protein peptide"J.Am.Chem.Soc.. 122・50. 12596-12597 (2000)

Yoshihiro Kuroda：“寡肽介导的朊病毒蛋白肽的α螺旋稳定化”J.Am.Chem.Soc. 122・50（2000）。

Kazuhide Miyamoto: "Solution structurs of the cytoplasmic linkers between segments S4 and S5(S4-S5)in domains III and IV of human brain sodium Channels in SDS micelles"J.Peptide Res.. 58・3. 193-203 (2001)

Kazuhide Miyamoto：“SDS胶束中人脑钠通道的结构域III和IV中的S4和S5片段之间的细胞质连接体(S4-S5)的溶液结构”J.Peptide Res. 58・3 (2001)。