Development of prophylactic and therapeutic anti-prion drugs for the patients at high risks

在日本，医源性Creutzfeldt-Jacob病（CJD）或遗传性朊病毒病频繁发生，需要开发朊病毒病的预防和治疗。本研究不仅包括基础研究，还包括临床应用的治疗开发，并阐明了以下几点：1.利用朊病毒感染细胞筛选，发现了许多抗朊病毒的化合物。发现了包括多种临床药物在内的约20种有效的喹啉类化合物，发现了80多种苯并噻唑类或刚果红类化合物的有效化合物，其中一些化合物不仅可作为治疗药物，而且可作为朊病毒成像探针，在疾病动物模型外周给药时，可检测朊病毒蛋白在脑内的异常沉积。戊聚糖多硫酸酯（SPS）和肝素衍生物也被发现是显着有效的。特别是SPS是最有益的 ...更多信息 一方面，朊蛋白（PrP）与抗朊蛋白化合物之间的相互作用分析表明，大多数抗朊蛋白化合物通过直接与PrP相互作用，抑制PrP的异常转化而发挥抗朊蛋白活性;结果表明，亲和性与抗朊病毒活性之间存在一定的相关性，可用于高通量筛选抗朊病毒药物。此外，抗朊病毒化合物的抗朊病毒活性依赖于感染细胞类型和病原体菌株。2. SPS在动物模型中显示出最有益的效果，在检查了其在实验动物中持续脑室内输注的安全性后，对一名患有变异型CJD的英国患者进行了实验治疗。尽管他的晚期临床阶段，脑室内SPS管理表现出更突出的效果比预期的，它没有表现出任何不良反应。在病人身上的发现，以及在动物模型实验中的发现，表明这种治疗也可以用来预防朊病毒疾病的高危人群。少

In Japan, where iatrogenic Creutzfeldt-Jacob disease (CJD) or hereditary prion disease has occurred frequently, development of prophylaxis and therapeutics for prion diseases has been required. This research covered not only the basic research but also the clinical application of the therapeutic development, and the following points were clarified.1.Many anti-prion compounds were discovered by screening with prion-infected cells. About 20 effective quinoline-ring vhemicals including several clinical medicines were found. More than 80 effective compaunds from benzothiazole-related chemicals or Congo red-related chemicals were discovered, and some of them were effective not only as therapeutic drugs but also as prion imaging probes capable of detecting abnormal prion protein deposition in the brain, when administered peripherally in the disease animal models. Pentosan polysulfate (SPS) and heparin derivatives were also found to he remarkably effective. Especially SPS was the most benefic … More ial, when administered intracerebroventricularly into the diseased animals.On the one hand, interaction analyses between prion protein (PrP) and anti-prion chemicals revealed that most of the anti-prion chemicals exert their anti-prion activities by interacting directly with the PrP and thus inhibiting the abnormal conversion. Correlation between the interaction affinity and the anti-prion activity was demonstrated and thus wan possibly applied to high-throughput screening for anti-prion chemicals. Furthermore, it was shown that anti-prion activities of the anti-prion chemicals were dependent of infected cell types as well as pathogen strains.2.About SPS which showed the most beneficial effects in the animal models, after checking the safety of its continuous intracerebroventricular infusion in experimental animals, experimental treatment was carried out in one British patient with variant CJD. In spite of his advanced clinical stage, intracerebroventricular SPS administration demonstrated more outstanding effects than expected, and it did not show any adverse effects. The findings in the patient, together with the findings in the animals model experiments, indicate that this treatment can be also used to prevent high-risk people from prion diseases. Less