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

心力衰竭和心脏病发作在2型糖尿病患者中更常见，尽管目前有最好的临床管理，但结果非常差。这是因为心脏含有大量的纤维物质（纤维化），这些纤维物质在心肌中积累，影响了心肌向全身泵血的能力，这种情况被称为糖尿病心肌病。拟议的项目旨在通过抑制多功能酶蛋白质转氨酶2（TG 2）的活性来克服这一问题。TG 2通过将某些蛋白质交联在一起“像胶水一样”促进纤维材料在心脏中的沉积增加而促进纤维化的发展。这种“蛋白质网”现在对重塑具有高度抵抗性，正常组织修复受到损害，这可能导致心力衰竭。阿斯顿的初步工作已经产生了抑制TG 2的强大化学物质，并可以开发成阻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。我们的目标是在这一早期工作的基础上，寻求进一步改善我们的早期TG2抑制剂化合物的药物特性。我们的最终目标是产生准备在动物中测试的TG2抑制化合物（以证明它们有效，并且不会引起危险的副作用）并且还将这些抑制剂进展为候选药物，该候选药物可以施用于人类患者以预防纤维化的进展并降低纤维化的发生率。糖尿病性心肌病患者的心力衰竭和心脏病发作。

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.