Chemical Tools to Interrogate Protein-Misfolding Diseases

研究蛋白质错误折叠疾病的化学工具

• 批准号: 2881377
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2881377
• 关键词: Chemical; Tools; Interrogate; Protein; Misfolding

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).

尽管学术界和工业界进行了长期和深入的研究，但阿尔茨海默病、帕金森病、2型糖尿病和其他淀粉样病变的发病机制、早期诊断和治疗仍然面临着挑战。这些疾病的一个标志是存在错误折叠的蛋白质，其中充满了功能失调的毒性状态。现有的治疗方法集中于减少蛋白质的产生和破坏淀粉样蛋白的聚集，取得的成功非常有限。为了解决这些疾病，需要更好地了解这些疾病背后的基础科学。蛋白质序列、构象动力学及其多种淀粉样变性之间的关系尚未得到充分的探讨。我们已经证明了使用结构引导合理设计的化学工具选择性识别纤维前淀粉样蛋白的特定构象状态，例如参见Chem comm(2022) 58,5132。利用最近淀粉样蛋白多态性的原子水平结构信息的爆炸，例如参见JMB(2021) 433, 167,124，该项目将专注于设计，合成和测试合成分子，这些分子可以模板或抑制特定多态性的形成，从而允许使用ThT， CD和AFM进行彻底的生物物理调查。我们将探索利用这些分子作为合成伴侣来调节蛋白质行为，表征对组装动力学及其结构组织的影响。这种变革性技术将为抑制有害淀粉样蛋白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。具体靶点将包括Abeta（阿尔茨海默氏症）、α -突触核蛋白（帕金森症）和IAPP（2型糖尿病）。