Research Projects

Diabetes is a chronic metabolic disease affecting over 95% of the global population, with type 2 diabetes (T2D) being a significant pathological feature. The misfolding and aggregation of human amylin (hAM) into β-sheet enriched oligomers and amyloid fibrils is a pathological feature in T2D. studies have shown that Cu2+-containing intermediate species of hAM display higher cytotoxicity, leading to the formation of reactive oxygen species (ROs) such as hydroxyl radicals (OH*) and hydrogen peroxide (H2O2) that lead to cell death by apoptosis. These studies suggest that inhibition of hAM aggregation alone is insufficient for T2D treatment, and more efficacious multifunctional modulators need to be developed to find potential candidates against multifactorial diseases like T2D. The aim is to design, synthesize, and evaluate multifunctional peptides (MFPs) to target various pathological hallmarks of T2D. The MFPs will be conjugated with metal (Cu2+, Zn2+) chelating agents, selected from the peptide libraries of NFGAILss and sTNVGs fragments of hAM using an integrated computational approach followed by in vitro evaluation. The selected Cu2+ chelating agent should selectively bind Cu2+ ions in the presence of other metal ions and selectively chelate Cu2+ ions from the hAM-Cu2+ complex compared to biologically important proteins/enzymes possessing copper. The synthesized MFPs will be evaluated for their ability to chelate metal ions, halt the generation of ROs, and inhibit the formation of hAM oligomers using biophysical techniques. MD simulations will be performed to gain insights into the molecular mechanism by which MFPs inhibit hAM aggregation and destabilize hAM protofibrils.