People with Type 2 diabetes are far more likely to develop heart failure because a glue-like enzyme called Transglutaminase 2 (TG2) locks fibrous material into the heart muscle, stiffening it until it can no longer pump blood effectively. This condition—diabetic cardiomyopathy—is poorly treated by current therapies. The enzyme TG2 crosslinks proteins into a rigid mesh that resists the heart’s normal repair processes. Researchers at Aston University have already developed chemical compounds that block TG2’s crosslinking action. This project aims to refine those compounds into drug candidates with better safety and potency. If successful, the work would produce TG2 inhibitors ready for testing in animals, and eventually in human patients. The goal is to halt or reverse the accumulation of fibrous tissue in the heart, reducing the incidence of heart failure and heart attacks in people with Type 2 diabetes. This would directly address a major cause of poor outcomes in a large and growing patient population, without requiring a complete overhaul of existing diabetes care.
View original technical description
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.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know