Development and pharmacological analysis of therapeutic drugs for conformation diseases and prion diseases

本研究的目的不仅是开发预防和治疗各种构象疾病的药物，如普鲁恩病、阿尔茨海默病和淀粉样变性，而且阐明作用于异常构象蛋白的药物的药理作用。通过三种体外试验，筛选出许多无神经毒性、有效抑制每种淀粉样蛋白聚集和神经毒性的候选化合物。这些化合物包括喹啉类化合物、苯并噻唑类化合物、非喹啉螯合化合物、刚果红相关化合物、硫酸多糖等。通过表面等离子体共振或圆二色谱研究了候选化合物对淀粉样蛋白多肽的作用机制。结果表明，大多数化学物质可以与…疏水口袋中核心β-折叠结构的疏水氨基酸序列相互作用更多的是淀粉样蛋白。他们还表明，这些化学物质的疏水结合强度与抑制淀粉样蛋白聚集的有效性相关，但并不总是与抑制神经毒性的有效性相关。在三种构象疾病模型小鼠中检测了几种渗透到大脑的化学物质。结果表明，化合物A口服给药是安全有效的预防和治疗药物，而化合物MC一次皮下注射更安全，在预防和治疗方面是最有益的。然而，体内有一些无效的化学物质，甚至很容易渗透到大脑，结合到由异常构象蛋白组成的沉积上。多个体外和体内实验表明，这种不一致可能是由于异常蛋白质和宿主因子(S)的构象变化引起的。研究结果表明，构象疾病药物的开发研究现在已经为下一阶段的翻译研究做好了准备。较少

This research was aimed to not only develop prophylactic and therapeutic drugs for any type of conformation diseases such as prion diseases, Alzheimer's disease and amyloidoses, but also clarify the pharmacology of the drugs acting on the abnormal conformation proteins.Using three in-vitro assays, candidate chemicals were screened, and many potent candidates which were non-neurotoxic and effective to inhibit both the aggregation of each amyloidotic protein and the neurotoxicity. These included quinoline compounds, benzothiazole compounds, non-quinoline chelatirig chemicals, Congo red related chemicals, sulfated polysaccharides and so on.The mechanism of action by the candidate chemicals on amyloidotic peptides derived from each of the amyloidotic proteins was examined by either surface plasmon resonance or circular dicroism. The results suggested that most of the chemicals could interact with a hydrophobic amino acid sequence of the core beta sheet structure in a hydrophobic pocket of … More the amyloidotic proteins. They also showed that strength of hydrophobic bonding by the chemicals was correlated with effectiveness in inhibiting the aggregation of the amyloidotic proteins but was not always correlated with effectiveness in inhibiting the neurotoxicity.Several of the chemicals which penetrated into the brain were assayd in three types of conformation disease model mice. The results showed that compound A in per oral administration was safe and very effective as a prophylactic and therapeutic drug, and also compound MC in even one shot subcutaneous administration was much safer and the most beneficial in the prophylaxis and therapeutics. However, there were some ineffective chemicals in vivo which even easily penetrated into the brain and bound to the depositions composed of the abnormal conformation proteins. Several in-vitro and in-vivo experiments suggested that this inconsistency might be caused by conformational variety of the abnormal proteins and host factor(s).The findings of the research indicate that the research for the development of conformation disease medicine is now ready for the next stage of translational research. Less