Characterisation of the Z-pocket for the treatment of alpha-1-antitrypsin deficiency

用于治疗 α-1-抗胰蛋白酶缺乏症的 Z 型袋的表征

• 批准号: MR/L017431/1
• 负责人: James Huntington
• 金额: $ 67.93万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL017431%2F1
• 关键词: Characterisation; pocket; treatment; alpha; antitrypsin

Alpha-1-antitrypsin (a1AT) deficiency is a relatively common genetic disorder resulting in lung and liver diseases, such as emphysema, cirrhosis and cancer. There is currently no cure or treatment. The most common cause is the 'Z' mutation which leads to the accumulation of misfolded a1AT 'polymers' in liver cells. As part of a previous MRC grant, we discovered a surprising mechanism of Z-a1AT polymerization and the structural feature that causes Z-a1AT to misfold. The goal of the current research is to study the feature, that we named the 'Z-pocket', in more detail. Compounds that bind to the Z-pocket could rescue the folding of Z-a1AT and effectively cure the disease. We will use X-ray crystallography and nuclear magnetic resonance to determine the properties of the Z-pocket and to see if previously identified compounds rescue folding by filling the pocket. Successful completion of this project will set the stage for the discovery of new drugs for the treatment of a1AT-deficiency.

α-1-抗胰蛋白酶（α 1AT）缺乏症是一种相对常见的遗传性疾病，导致肺和肝脏疾病，如肺气肿、肝硬化和癌症。目前没有治愈或治疗方法。最常见的原因是“Z”突变，其导致肝细胞中错误折叠的a1 AT“聚合物”的积累。作为先前MRC资助的一部分，我们发现了Z-a1 AT聚合的惊人机制和导致Z-a1 AT错误折叠的结构特征。当前研究的目标是更详细地研究我们命名为“Z-pocket”的功能。与Z口袋结合的化合物可以拯救Z-a1 AT的折叠并有效地治疗疾病。我们将使用X射线晶体学和核磁共振来确定Z口袋的性质，并看看以前鉴定的化合物是否通过填充口袋来拯救折叠。该项目的成功完成将为发现治疗a1 AT缺乏症的新药奠定基础。