Exploring the Impact of C‐Terminal Based Pentapeptides on the Disassembly of Aβ42 Fibrils

Abstract 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 42 aggregation as compared to Aβ 42 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 42 protofibril was assessed by molecular dynamics (MD) simulations and in vitro studies. The binding free energy analysis depicts that charged residues influence Aβ 42 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 42 protofibril. RVVPI exhibited highest inhibitory activity (Inhibition=66.2 %, IC 50 =5.57±0.83 μM) against Aβ 42 aggregation consistent with computational results. Remarkably, RVVPI displayed ~4.5 fold lower IC 50 value as compared to RIIGL. ThT and TEM studies highlighted the enhanced efficiency of RVVPI (62.4 %) in the disassembly of pre‐formed Aβ 42 fibrils than RIIGL and RIAPA. The combined in silico and in vitro studies identified a new peptide, RVVPI, as an efficient inhibitor of Aβ 42 fibrillation and disassembly of Aβ 42 aggregates.