散发性致死性失眠的药物治疗综述。
A review of drug therapy for sporadic fatal insomnia.
作者信息
Tabaee Damavandi Pardis, Dove Martin T, Pickersgill Richard W
机构信息
a Queen Mary University of London , School of Biological and Chemical Sciences , London , UK.
b Queen Mary University of London , School of Physics and Astronomy , London , UK.
出版信息
Prion. 2017 Sep 3;11(5):293-299. doi: 10.1080/19336896.2017.1368937.
BACKGROUND
Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death. The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet.
METHODS
We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety".
CONCLUSION
As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening.
背景
散发性致死性失眠症（sFI）是一种快速进展的神经退行性疾病，其特征是从逐渐失眠发展为持续性失眠，随后出现自主神经功能障碍、昏迷和死亡。sFI的病因最近被定位到人脑中发现的一种蛋白质——朊病毒的突变。正是朊病毒的展开导致了有毒低聚物的产生，这些低聚物会破坏脑组织和功能。最近的研究证实，人类朊病毒第129密码子处的甲硫氨酸突变是sFI的特征。目前的治疗方法减缓了疾病的进展，但尚未找到治愈方法。
方法
我们使用分子对接和分子动力学模拟方法，研究局部展开时有毒的致死性失眠症朊病毒构象。目的是确定这些位点，并使用基于吩噻嗪“部分”的小分子配体来稳定这些区域，防止其展开和错误折叠。
结论
因此，我们在此讨论当前的致死性失眠症治疗方法，并提出七种新型化合物用于体外和体内筛选。
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