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

为高危患者开发预防性和治疗性抗朊病毒药物

基本信息

批准号：
13557118
负责人：
DOH-URA Katsumi
金额：
$ 8.51万
依托单位：
Tohoku University (2003)Kyushu University (2001-2002)
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

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557118/
关键词：
prion disease prophylactic and therapeutic medicine inhibition of prion biosynthesis drug screening persistently infected cell culture animal experiment pentsan polysulfate intracerebroventricular administration スクリーニング脳内感染脳室内持続注入

项目摘要

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

在日本，医源性克雅氏病（CJD）或遗传性朊病毒病经常发生，因此需要开发朊病毒疾病的预防和治疗方法。本研究不仅涵盖了基础研究，也涵盖了治疗发展的临床应用，并阐明了以下几点：1。通过对朊病毒感染细胞的筛选，发现了许多抗朊病毒化合物。发现约20种有效的喹啉环化学物质，包括几种临床药物。从苯并噻唑相关化学物质或刚果红相关化学物质中发现了80多种有效化合物，其中一些化合物在疾病动物模型中外周给药时，不仅可以作为治疗药物，而且可以作为朊病毒成像探针，能够检测大脑中异常的朊病毒蛋白沉积。聚硫酸戊聚糖（SPS）和肝素衍生物也有显著效果。特别是SPS是最有益的…更重要的是，当给病动物脑室内施用。一方面，朊病毒蛋白（PrP）与抗朊病毒化学物质的相互作用分析表明，大多数抗朊病毒化学物质通过与PrP直接相互作用来抑制异常转化，从而发挥其抗朊病毒活性。相互作用亲和力与抗朊病毒活性之间存在相关性，因此有可能用于抗朊病毒化学物质的高通量筛选。此外，抗朊病毒化学物质的抗朊病毒活性依赖于感染细胞类型和病原体菌株。关于在动物模型中表现出最有益效果的SPS，在实验动物连续脑室灌注验证其安全性后，对1例英国变异型CJD患者进行了实验治疗。尽管他的临床阶段较晚，但脑室内给药SPS的效果比预期更突出，没有出现任何不良反应。在病人身上的发现，以及在动物模型实验中的发现，表明这种治疗方法也可用于预防高危人群感染朊病毒疾病。少