Development of a high-pressure treatment for amyloidosis

淀粉样变性高压治疗方法的开发

基本信息

批准号：
13558082
负责人：
TACHIBANA Hideki
金额：
$ 7.62万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

1. A disulfide-deficient variant of hen lysozyme self-associates into a 17-S assemblage that contains intermolecular beta-structure. Upon prolonged incubation over weeks to months, amyloid-like fibrils are spontaneously formed. No specific, partially unfolded conformer is involved, and fibrils are formed starting from an intrinsically unfolded monomeric state and passing through a precursor with a spontaneous build-up of intermolecular beta-structure.2. The 17-S precursor reversibly dissociates under hydrostatic pressure of several hundred to two thousand bars. It is characterized with a Gibbs energy for association of -23.3 kJ and a volume increase of 52.7 ml per mol of monomer unit, and involves interaction of hydrophobic residues in the initial association step.3. By carrying out two-dimensional NMR measurements under variable pressure, a metastable conformer of the normal cellular isoform of prion protein (PrP^c) has been found to occur at a population of 1 %, in which helices B an … More d C are disordered. This metastable conformer is most logically PrP^* that is implicated in the step for transformation of PrP^c to the infectious prion protein (PrP^<Sc>) via interaction with a template PrP^<Sc>. On the other hand, the conformational characteristics of a fibril-forming fragment of the mouse prion protein have been investigated by using hydrogen-deuterium exchange measurements and molecular dynamics simulations. Fibril formation was shown to involve polyalanine stacking.4. There exists a correlation for prion protein between the residue-wise stability determined by high-pressure NMR spectroscopy and slow fluctuations determined by the CPMG method at ambient pressure. This indicates that the metastable conformer revealed by high-pressure NMR can be acquired through slow conformational fluctuations under physiological conditions. Cavities exist at the site of large fluctuation, which strongly suggests that the screening for the molecules that bind to the cavity leads to the development of drugs for the treatment of prion disease or amyloidosis. Less

1。溶菌酶自我缔合的二硫化物缺陷在17-s的组合中，分子间的β结构在数周到几个月内孵化。原纤维从本质上展开的状态开始，并通过ARβ结构的前体经过。2。在初始关联步骤中的52.7 ml单体单位摩尔单体单位，水中恐惧症残基3。发现发生在1％d c c的种群中，这与Prp^另一方的转化步骤相关，这是小鼠蛋白蛋白质蛋白质形成的纤维形成片段的共置特征，该特征是通过使用氢 - 偏度测量和分子动力学模拟的。表现出涉及多酰胺的堆积。4。开发用于治疗病毒疾病或淀粉样变性的药物。