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

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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.