Prion Disease Therapeutics

传染性海绵状脑病（tse或朊病毒疾病）是一种致命的无法治愈的神经退行性疾病，如痒病、克雅氏病（CJD）、牛海绵状脑病和慢性消耗性疾病（CWD）。TSE的发病机制涉及一种被称为PrPres的异常蛋白在被感染宿主体内的积累。我们和其他人之前发现了各种线性或支链硫酸聚合物，它们可以有效地抑制PrPres的积累，减缓或防止实验动物瘙痒病的进展。然而，这些大的带电聚合物在外周给药后很难穿过血脑屏障进入大脑。因此，我们一直在寻找这种更小的分子，它可能是有效的PrPres抑制剂，同时对受感染个体具有更好的生物利用度或更低的毒性。为了实现这一目标，我们测试了几种硫酸环糊精，发现其中一些是瘙痒病感染组织培养细胞中PrP-res积累的优秀抑制剂。

The transmissible spongiform encephalopathies (TSEs or prion diseases)are fatal untreatable neurodegenerative diseases such as scrapie, Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy and chronic wasting disease (CWD). TSE pathogenesis involves the accumulation of an abnormal protein, called PrPres, in infected hosts. We and others previously identified a variety of linear or branched sulfated polymers that are effective in inhibiting PrPres accumulation and slowing or prevent the progression of scrapie in experimental animals. However, these large charged polymers have difficulty crossing the blood-brain barrier to enter the brain after peripheral administration. We have therefore sought smaller molecules of this sort that might be effective PrPres inhibitors while having better bioavailability or lower toxicity in infected individuals. Toward this goal, we tested several sulfated cyclodextrins and found that some were excellent inhibitors of PrP-res accumulation in scrapie-infected tissue culture cells.