Research Projects

Alzheimer’s disease (AD) is a complex neurodegenerative disease characterized by misfolding of amyloid–β (Aβ) peptide that hinders the usual functioning of the brain. Histopathologically, AD comprises Aβ deposits, neurofibrillary tangles (τ aggregation), loss of cholinergic transmission, metal ion dyshomeostasis, an imbalance between the generation and removal of reactive oxygen species (ROS), and oxidative stress. Aβ generated through the amyloidogenic pathway has a high potential to aggregate and produce variable soluble and insoluble aggregated species through hydrophobic contacts. In addition, dyshomeostasis and miscompartmentalization of biometals like Cu2+, Fe2+, and Zn2+ also contribute to AD pathology. The metal ions form Aβ–metal complexes which augment the rate of aggregation and further intensify Aβ toxicity. The redox–active metal ions (Cu2+ and Fe2+) initiate Fenton–type reactions in the reducing environment and generate excessive ROS, which is responsible for oxidative stress, DNA damage, and neuronal cell death. Taking into account the multifactorial nature of AD, designing multi–target–directed ligands (MTDLs) is an effective approach for the treatment of AD. Molecules that inhibit Aβ aggregation or disrupt the preassembled Aβ aggregates have attracted great attention as potential drug candidates for AD. In particular, peptide-based inhibitors are of great interest as anti-aggregation antagonists due to their high target affinity, high specificity, promising biocompatibility, and low cytotoxicity. Thus, we aim to design, synthesize and evaluate multifunctional peptides (MFPs) to target various pathological hallmarks of AD. The design of MFPs will involve the conjugation of Aβ42 aggregation inhibitor with metal (Cu2+, Zn2+) binding peptides. In this direction, we aim to computationally design libraries of peptide inhibitors based on the Aβ42-derived sequences and screen the designed peptide libraries to identify new Aβ42 aggregation inhibitors using an integrated computational approach followed by in vitro evaluation. Using an integrated computational approach for screening the designed peptide library before solid phase peptide synthesis will save time, effort, and money in synthesizing the whole peptide library. The lead Aβ42 aggregation inhibitors identified using a computational screening approach followed by in vitro evaluation will be conjugated with Cu2+ chelating agents to yield new multifunctional peptides (MFPs) to modulate Aβ42/Cu2+–mediated aggregation, copper-induced cytotoxicity in AD. MFPs will be evaluated for the inhibitory activity against Aβ42/Cu2+–mediated aggregation and disaggregation of preformed Aβ42 fibrils by in vitro assays. The combined computational, biophysical, and biological studies will provide promising new MFPs as modulators of Aβ42/Cu2+-mediated aggregation and copper-induced cytotoxicity in AD.