Peptides and small molecules that influence prion disease

影响朊病毒病的肽和小分子

• 批准号: 6440477
• 负责人: FRED E COHEN
• 金额: $ 28.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6440477
• 关键词: antiinfective agents; chemical aggregate; conformation; cyclohexanones; drug design /synthesis /production; molecular pathology; peptide structure; prions; protein structure function; synthetic peptide

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.

也许朊病毒病最非正统的特征是这类神经退行性疾病的传染性、遗传性和散发性形式的共存。随着最近在英国出现新的变异型克-雅二氏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非常重要。基于结构的药物设计的工具将被用来确定合理的抑制剂的关键步骤（S）在朊病毒复制从PrPc的结构分析。初步工作已经确定了一系列的线索，研究其终止由分子间β-结构介导的多聚化的能力。最后，肽，能够诱导朊病毒神经病理学的构象依赖的方式将进行研究，以更好地了解朊病毒活性的分子要求。这些努力应该产生改进的检测朊病毒复制抑制剂。生物学家，合成化学家，计算生物化学家和生物化学家，计算生物化学家和生物化学家之间的密切合作，建议实现这些目标。治疗策略的成功开发应该对涉及蛋白质聚集的其他神经退行性疾病的治疗有影响。