Doh-ura Katsumi
Department of Prion Research, Tohoku University.
Rinsho Shinkeigaku. 2003 Nov;43(11):820-2.
Recent outbreaks of acquired forms of human prion diseases in younger people are promoting the development of prophylaxis and therapeutics. One possible target for therapeutic interventions is to inhibit the biosynthesis and accumulation of an abnormal isoform of prion protein, which is supposed to be a pathogen itself. Here, our current in-vitro and in-vivo data on anti-prion chemicals with amyloid binding capacity, represented by pentosan polysulfate and thioflavin-related chemicals, are presented, and structural aspects on the interaction between prion protein molecules and anti-prion chemicals including quinacrine are discussed. The current status of clinical trials using quinacrine or pentosan polysulfate is also reviewed. Finally, key structure(s) in the prion protein molecules, important to inhibit the conversion into abnormal prion protein molecules, are discussed in terms of pharmacology, and possibility of the in-silico rational drug design is also referred. Exploitation of anti-prion drugs should facilitate to solve the enigma of "prion" which can be the only creature against the central dogma, in addition to its contributing to the people with the illness or the people in high risks.
近期年轻人中出现的后天性人类朊病毒疾病疫情正在推动预防和治疗方法的发展。治疗干预的一个可能靶点是抑制朊病毒蛋白异常异构体的生物合成和积累,该异构体被认为本身就是病原体。在此,我们展示了目前关于具有淀粉样蛋白结合能力的抗朊病毒化学物质的体外和体内数据,这些化学物质以戊聚糖多硫酸盐和硫黄素相关化学物质为代表,并讨论了朊病毒蛋白分子与包括奎纳克林在内的抗朊病毒化学物质之间相互作用的结构方面。还综述了使用奎纳克林或戊聚糖多硫酸盐的临床试验现状。最后,从药理学角度讨论了朊病毒蛋白分子中对于抑制其转化为异常朊病毒蛋白分子至关重要的关键结构,并提及了计算机辅助合理药物设计的可能性。除了有助于患病者或高风险人群外,抗朊病毒药物的开发应有助于解开“朊病毒”这一可能是唯一违背中心法则的生物之谜。