Chemical Tools to Interrogate Protein-Misfolding Diseases

尽管学术界和工业界进行了长期而密集的研究计划，但阿尔茨海默氏症、帕金森氏症、II型糖尿病和其他淀粉样变性疾病的发病机制、早期诊断和治疗仍然没有得到满足。这些情况的一个特点是存在错误折叠的蛋白质，其中存在功能失调的毒性状态。现有的治疗方法集中在减少蛋白质产生和破坏淀粉样蛋白聚集物上，取得的成功非常有限。为了解决这些疾病，需要更好地理解这些疾病背后的基础科学。蛋白质序列、构象动力学和它们的多个淀粉样变性之间的关系还没有得到充分的研究。我们已经演示了使用结构指导的合理设计的化学工具来选择性识别纤维前纤维淀粉样蛋白的特定构象状态，例如参见Chem Commun(2022)58,5132。利用最近淀粉样多型体的原子级结构信息的爆炸性变化，例如参见JMB(2021)433,167,124，该项目将专注于设计、合成和测试可作为模板或抑制特定多型体形成的合成分子，从而允许使用THT、CD和AFM进行全面的生物物理询问。我们将探索使用这些分子作为合成伴侣来调节蛋白质的行为，表征对组装动力学和它们的结构组织的影响。这种变革性的技术将为抑制有害淀粉样结构形成的分子策略提供信息，从而推动生物科学发现的边界。具体的靶点将包括Abeta(阿尔茨海默氏症)、α-突触核蛋白(帕金森氏症)和IAPP(2型糖尿病)。

Despite prolonged and intensive research programmes in academia and industry, the pathogenesis, early diagnosis and treatment of Alzheimer's, Parkinson's, type II diabetes, and other amyloidopathies remain unmet challenges. A hallmark of these conditions is the presence of misfolded proteins in which dysfunctional toxic states are populated. Very limited success has been possible with extant therapeutic approaches that have concentrated on reducing protein production and disrupting amyloid aggregates. In order to tackle these maladies, an improved understanding of the basic science underlying the conditions is required. The relationship between protein sequence, conformational dynamics and their multiple amyloidogenic polymorphs has not been adequately explored. We have demonstrated selective recognition of specific conformational states of prefibrillar amyloigogenic proteins using structure guided rationally designed chemical tools, see for example Chem Commun (2022) 58, 5132. Leveraging the recent explosion in atomic level structural information of amyloid polymorphs, see for example JMB (2021) 433, 167,124, this project will focus on the design, synthesis and testing of synthetic molecules that template or inhibit the formation of specific polymorphs, thus allowing thorough biophysical interrogation using ThT, CD and AFM. We will explore the use of these molecules to modulate protein behaviour by acting as synthetic chaperones, characterising the effect on the kinetics of assembly and their structural organisation. Such transformative technologies will inform molecular strategies to inhibit formation of detrimental amyloid structures and thus push the boundaries of bioscience discovery. Specific targets will include Abeta (Alzheimer's), alpha-synuclein (Parkinson's) and IAPP (type 2 diabetes).