Developing Therapeutics for PrP Prion Diseases.
Developing Therapeutics for PrP Prion Diseases.
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DOI：
10.1101/cshperspect.a023747
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发表时间：
2017-04-03
影响因子：
5.4
通讯作者：
Prusiner SB
中科院分区：
文献类型：
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作者：
Giles K;Olson SH;Prusiner SB
典型的朊病毒疾病总是致命的，寻找可用于治疗它们的药物的研究跨越了30多年，但成功有限。然而，在过去的几年中，高通量筛选，药物化学和药代动力学优化的应用已经取得了重要进展。朊病毒接种模式提供了一种用于测试治疗功效的稳健测定，并且已经报道了十几种化合物，其导致朊病毒感染小鼠的存活期的有意义的延长。在这里，我们回顾了该领域的历史和最新进展，重点是已经在动物模型中验证的研究。基于在感染小鼠传代朊病毒的细胞中进行的筛选，已经产生了口服有效的化合物，其使感染相同朊病毒株的小鼠的存活率增加一倍甚至三倍。不幸的是，还没有化合物显示出对人朊病毒的功效。尽管如此，最近进展的速度带来了希望，可以开发出有效的治疗方法。任何神经退行性疾病的成功治疗都将是一项重大成就，并且越来越多的人认识到更常见的神经退行性疾病，包括阿尔茨海默氏症和帕金森氏症，通过类似的朊病毒机制进展，这突出了抗朊病毒疗法的重要性。
The prototypical prion diseases are invariably fatal, and the search for agents that can be used to treat them spans over 30 years, with limited success. However, in the last few years, the application of high-throughput screening, medicinal chemistry, and pharmacokinetic optimization have led to important advances. The prion inoculation paradigm provides a robust assay for testing therapeutic efficacy, and a dozen compounds have been reported that led to meaningful extension in survival of prion-infected mice. Here, we review the history and recent progress in the field, focusing on studies that have been validated in animal models. Based on screens in cells infected with mouse-passaged prions, orally available compounds have been generated that double or even triple the survival of mice infected with the same prion strain. Unfortunately, no compounds have yet shown efficacy against human prions. Nevertheless, the speed of the recent advances brings hope that an effective therapeutic can be developed. A successful treatment for any neurodegenerative disease would be a major achievement, and the growing understanding that the more common neurodegenerative diseases, including Alzheimer’s and Parkinson’s, progress by an analogous prion mechanism serves to highlight the importance of anti-prion therapeutics.