MICA: Novel inhibitors of Transglutaminase 2 (TG2), a new therapy to halt the progression of diabetic cardiomyopathy

MICA：新型转谷氨酰胺酶 2 (TG2) 抑制剂，一种阻止糖尿病心肌病进展的新疗法

• 批准号: MR/T005793/1
• 负责人: Martin Griffin
• 金额: $ 235.38万
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT005793%2F1
• 关键词: MICA; Novel; inhibitors; Transglutaminase; TG2

Heart failure and heart attacks are more frequent in people suffering from Type 2 diabetes and have exceptionally poor outcomes despite current best clinical management. This is because the heart contains increased amounts of fibrous material (fibrosis) which has accumulated in the heart muscle affecting its ability to pump blood around the body, a condition known as diabetic cardiomyopathy.The proposed project is aimed at overcoming this problem by inhibiting the activity of the multifunctional enzyme protein called Transglutaminase 2 (TG2). TG2 contributes to the development of fibrosis by crosslinking certain proteins together "like a glue" which facilitates the increased deposition of the fibrous material in the heart. This "protein mesh" is now highly resistant to remodelling and normal tissue repair is compromised which can lead to heart failure. Preliminary work at Aston has resulted in powerful chemicals that inhibit TG2 and could be developed into drugs that prevent the crosslinking glue-action thus, enabling the heart to remodel the damaged areas and form healthy tissue. We aim to build on this early work by seeking further improvements in the drug properties of our early inhibitor compounds of TG2 .Our ultimate goal is to generate TG2 inhibiting compounds that are ready to test in animals (to show that they work and that they do not cause dangerous side effects) and also to progress these inhibitors towards a candidate drug that can be administered to human patients to prevent the progression of fibrosis and reduce the incidence of heart failure and heart attacks in patients suffering from diabetic cardiomyopathy.

心力衰竭和心脏病发作在患有2型糖尿病的人中更常见，尽管目前最好的临床治疗方法，但结果非常糟糕。这是因为心脏含有更多的纤维物质(纤维化)，这些纤维物质在心肌中积累，影响其在全身泵血的能力，这种情况被称为糖尿病心肌病。拟议的项目旨在通过抑制名为转谷氨酰胺酶2(TG2)的多功能酶蛋白的活性来克服这个问题。TG2通过将某些蛋白质“像胶水一样”交联在一起，促进纤维物质在心脏中的沉积，从而促进了纤维化的发展。这种“蛋白质网”现在高度抵抗重塑，正常的组织修复受到损害，可能导致心力衰竭。阿斯顿的初步工作已经产生了抑制TG2的强大化学物质，并可能被开发成防止交联胶作用的药物，从而使心脏能够重塑受损区域并形成健康组织。我们的目标是在这项早期工作的基础上，寻求进一步改善我们早期TG2抑制剂化合物的药物性质。我们的最终目标是产生准备在动物身上试验的TG2抑制剂化合物(证明它们有效，并且不会造成危险的副作用)，并将这些抑制剂进展为可以用于人类患者的候选药物，以防止纤维化的进展，并减少糖尿病心肌病患者的心力衰竭和心脏病发作的发生率。