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

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