Peptides and small molecules that influence prion disease

也许朊病毒病最非正统的特征是感染性、遗传性和散发性这类神经退行性疾病的共存。随着最近在英国发生的新型克雷茨费尔特-雅各布病及其与疯牛病的联系，了解这类疾病的分子基础并开始开发治疗药物是很重要的。基于结构的药物设计工具将用于从PrPc的结构分析中确定朊病毒复制关键步骤的合理抑制剂。初步的工作已经确定了一系列引线，研究了它们终止由分子间结构介导的多聚合的能力。最后，能够以构象依赖的方式诱导朊病毒神经病理的肽将被研究，以更好地了解朊病毒活性的分子要求。这些努力将产生改进的朊病毒复制抑制剂测定方法。生物学家、合成化学家、计算生物物理学家和生化学家、计算生物物理学家和生化学家之间的密切合作被提议来实现这些目标。治疗策略的成功发展应该对其他涉及蛋白质聚集的神经退行性疾病的治疗具有启示意义。

Perhaps the most unorthodox feature of prion disease is the co-existence of infectious, genetic and sporadic forms of this class of neurodegenerative diseases. With the recent occurrence of new variant Crretzfeldt-Jakob disease in the United Kingdom and the link to Mad Cow disease, it is important to understand the molecular basis of this class of diseases and begin to develop therapeutic agents. The tools of structure based drug design will be used to identify plausible inhibitors of key step(s) in prion replication from an analysis of the structure of PrPc. Preliminary work has identified a collection of leads studied for their ability to terminate multi-merization mediated by intermolecular beta- structure. Finally, peptides that are capable of inducing prion neuropathology in a conformation dependent fashion will be studied to better understand the molecular requirements for prion activity. These efforts should yield improved assays for inhibitors of prion replication. A close collaboration between biologists, synthetic chemists, computational biophysicists and biochemists, computational biophysicists and biochemists is proposed to achieve these goals. Success in the development of therapeutic strategies should have implications for the treatment of other neurodegenerative diseases that involve protein aggregation.