Total protein synthesis: a new tool for studies of the structure and stability of amyloid fibrils

全蛋白合成：研究淀粉样原纤维结构和稳定性的新工具

• 批准号: BB/D000807/1
• 负责人: Stuart Warriner
• 金额: $ 29.64万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD000807%2F1
• 关键词: Total; protein; synthesis; new; tool

Amyloid diseases include many well known conditions such as Alzheimer's disease and new variant Cruetzfeld-Jakob disease. All these conditions involve the aggregation of protein molecules into large insoluble fibrils. The purpose of this research is to understand how proteins assemble into amyloid fibrils at the molecular level. We aim to achieve this by altering the structure of beta-2-microglobulin, a protein involved in an amyloid condition that affects all people on long-term renal dialysis, and to investigate how the changes to the protein sequence alter the ability of the protein to form amyloid fibrils. In this particular study we will make changes to the fundamental backbone structure of the protein and such manipulations can not be made using biochemical methods. Instead we will synthesise the whole protein structure using chemistry making each amide bond in a laboratory reactor. The chemical approach does not have the same limitations as biochemistry and so we can make profound changes to the fundamental structure of the target protein. By studying how these changes to the protein structure alter its ability to form amyloid fibres we will elucidate new information about the structure and stability of amyloid fibrils that will inform future work to develop new therapies against these fatal diseases.

淀粉样蛋白疾病包括许多众所周知的疾病，如阿尔茨海默病和新型克鲁茨菲尔德-雅各布病。所有这些条件都涉及蛋白质分子聚集成大的不溶性原纤维。本研究的目的是了解蛋白质如何在分子水平上组装成淀粉样原纤维。我们的目标是通过改变β -2微球蛋白（一种影响所有长期肾透析患者的淀粉样蛋白）的结构来实现这一目标，并研究蛋白质序列的变化如何改变蛋白质形成淀粉样蛋白原纤维的能力。在这个特殊的研究中，我们将改变蛋白质的基本骨干结构，这种操作不能用生化方法进行。相反，我们将用化学方法合成整个蛋白质结构，在实验室反应器中制造每个酰胺键。化学方法不像生物化学那样有局限性，因此我们可以对目标蛋白质的基本结构进行深刻的改变。通过研究蛋白质结构的这些变化如何改变其形成淀粉样纤维的能力，我们将阐明有关淀粉样原纤维结构和稳定性的新信息，这将为未来开发针对这些致命疾病的新疗法提供信息。

项目成果

Avoidance of epimerization in the synthesis of peptide thioesters using Fmoc protection

• DOI: 10.1055/s-2007-986631
• 发表时间: 2007-10-01
• 期刊: SYNLETT
• 影响因子: 2
• 作者: Nagalingam, Anil C.;Radford, Sheena E.;Warriner, Stuart L.
• 通讯作者: Warriner, Stuart L.

Phosphorylation as a tool to modulate aggregation propensity and to predict fibril architecture.

• DOI: 10.1002/cbic.201100607
• 发表时间: 2012-01-23
• 期刊: CHEMBIOCHEM
• 影响因子: 3.2
• 作者: Valette, Nathalie M.;Radford, Sheena E.;Harris, Sarah A.;Warriner, Stuart L.
• 通讯作者: Warriner, Stuart L.