Design and Development of Proteasome Activity Modulators: A Novel Strategy for the Treatment of Diabetes Mellitus

Abstract

Design and Development of Proteasome Activity Modulators: A Novel Strategy for the Treatment of Diabetes Mellitus

Abstract The ubiquitin-proteasome system (UPS) is the major pathway for degradation of the intracellular proteins and it also plays a vital role in protein homeostasis. The proteasome is a multi-catalytic enzyme complex found in nucleus and cytoplasm of all eukaryotic cells. The proteasome not only degrades damaged, oxidized, or misfolded proteins but also plays a vital role in degrading proteins that regulate the cell cycle, activate transcription factors and control cell growth. When accumulation of disordered or oxidatively damaged proteins exceeds proper clearance in neurons, imbalanced pathway signaling or aggregation occurs, which have been implicated in the pathogenesis of several diseases. The diabetes mellitus has been characterized by the hyperglycaemia or the failure of insulin secretion and uptake. The research has revealed that there is large accumulation of misfolded and damaged proteins in stress environment, which result in decline of insulin secretion or insulin uptake. The novel strategy for the treatment of the diabetes is the clearance of these proteins that brings the cell in normal protein homeostasis. The proteasome plays a pivotal role in clearance of proteins. The proteasome activity modulation is technique that can be used for the treatment of several diseases, but research suggest that we need to activate the proteasome to clear the excess of unwanted proteins to restore the normal protein homeostasis. Therefore, based on the activators known and the biological significance of amino acids in the body, we have designed the novel proteasome activators. In my thesis defence, I will discuss about the proteasome-structure, functions, and mechanism of action. The different type of diabetic mellitus and the role of proteasome in the stress and normal environment. The design strategy for treatment of diabetes mellitus and the various studies on the compounds synthesized. REFERENCES: 1. López-Otín, Carlos, and Judith S. Bond. Journal of Biological Chemistry 283.45 (2008): 30433-30437. 2. Tanaka, Keiji. Proceedings of the Japan Academy, Series B 85.1 (2009): 12-36. 3. Adams, Julian. Cancer treatment reviews 29 (2003): 3-9. 4. Kharroubi, Akram T., and H. M. Darwish. World journal of diabetes 6.6 (2015): 850. 5. Thomaidou, Sofia, Arnaud Zaldumbide, and Bart O. Roep. Diabetes, Obesity and Metabolism 20 (2018): 88-94.