Peptides and small molecules that influence prion disease

可能Pron病最非正统的特征是这类神经退行性疾病的感染性、遗传性和零星形式共存。随着最近英国出现新的CrretzFeldt-Jakob病变异以及与疯牛病的联系，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被用来从PrPc的结构分析中确定PrPc关键步骤(S)的合理抑制剂。初步工作已经确定了一系列因其终止分子间β-结构介导的多重聚合的能力而被研究的先导化合物。最后，将研究能够以构象依赖的方式诱导普恩病毒神经病理的多肽，以更好地了解普恩蛋白活性的分子要求。这些努力应该会改进普鲁恩复制抑制物的检测方法。生物学家、合成化学家、计算生物物理学家和生物化学家、计算生物物理学家和生物化学家之间的密切合作就是为了实现这些目标。治疗策略的成功开发应该会对其他涉及蛋白质聚集的神经退行性疾病的治疗产生影响。

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.