Exploring the Impact of C-Terminal Based Pentapeptides on the Disassembly of Aß42 Fibrils.

ABSTRACT

An effective therapeutic strategy to suppress Alzheimer's disease (AD) progression is to disrupt ß-sheet rich neurotoxic soluble amyloid-ß (Aß) aggregates. Previously, we identified new pentapeptides (RVVPI and RIAPA) with notably enhanced ability to block Aß42 aggregation as compared to Aß42 C-terminal derived peptide RIIGL using integrated computational protocol. In this work, the potential of RIIGL, RVVPI, and RIAPA for the structural destabilization of Aß42 protofibril was assessed by molecular dynamics (MD) simulations and in vitro studies. The binding free energy analysis depicts that charged residues influence Aß42 protofibril-pentapeptide interactions. Notably, RVVPI displays a more pronounced destabilization effect than other peptides due to higher conformational fluctuations, and disruption of salt bridge (K28-A42) interactions in Aß42 protofibril. RVVPI exhibited highest inhibitory activity (Inhibition= 66.2%, IC50= 5.57 ± 0.83 µM) against Aß42 aggregation consistent with computational results. Remarkably, RVVPI displayed ~4.5 fold lower IC50 value as compared to RIIGL. ThT and TEM studies highlighted the enhanced efficiency of RVVPI (62.4%) in the disassembly of pre-formed Aß42 fibrils than RIIGL and RIAPA. The combined in silico and in vitro studies identified a new peptide, RVVPI, as an efficient inhibitor of Aß42 fibrillation and disassembly of Aß42 aggregates.