Prion Disease Therapeutics

朊病毒病治疗

• 批准号: 7964735
• 负责人: BYRON CAUGHEY
• 金额: $ 10.83万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7964735
• 关键词: Animals; Biological Availability; Blood - brain barrier anatomy; Bovine Spongiform Encephalopathy; Brain; Charge; Chronic Wasting Disease; Creutzfeldt-Jakob Syndrome; Cyclodextrins; Disease; Goals; Human; Individual; Inorganic Sulfates; Neurodegenerative Disorders; Pathogenesis; Peripheral; Polymers; PrPSc Proteins; Prion Diseases; Proteins; Scrapie; Sheep; Sorting - Cell Movement; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Unspecified or Sulfate Ion Sulfates; cervid; inhibitor/antagonist; novel therapeutics; prevent; small molecule; sulfated polymer; tissue/cell culture

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.

可传播的海绵状脑病（TSE或PRION疾病）是致命的不可治疗的神经退行性疾病，例如Crapie，Creutzfeldt-Jakob病（CJD），牛spongine Spongiorment spongiorment Chiormanty和慢性浪费疾病（CWD）。 TSE发病机理涉及被感染宿主中称为PRPRE的异常蛋白的积累。我们和其他人以前鉴定出各种线性或分支硫化聚合物，这些聚合物可有效抑制PRPRES的积累，放缓或防止实验动物中的crap虫的进展。但是，这些大型电荷聚合物在外周施用后难以穿越血脑屏障进入大脑。因此，我们寻求这种较小的分子，这些分子可能是有效的PRPRES抑制剂，同时具有更好的生物利用度或较低的感染者毒性。为了实现这一目标，我们测试了几个硫化的环糊精，发现有些是PRP-RES积累的极好的抑制剂，在冰草感染的组织培养细胞中。