Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, marked by the accumulation of amyloid-β (Aβ) plaques in the brain, excessive tau protein phosphorylation, and cholinergic neuron degeneration. In this work, a library of computationally designed peptides based on the Aβ42 recognition sequence KLVFF has been generated, which is further evaluated for its ability to effectively attenuate Aβ42 fibrillation. Notably, molecular mechanics Poisson-Boltzmann surface area analysis identified three new peptides, RPPWF (ΔGbinding = -58.08 ± 9.02 kcal/mol), RPPWY (ΔGbinding = -46.13 ± 3.62 kcal/mol), and KPPWW (ΔGbinding = -44.27 ± 4.08 kcal/mol), displaying significantly higher binding affinity to the Aβ42 monomer (Aβ42m) compared to KLVFF (ΔGbinding = -38.70 ± 17.17 kcal/mol). Importantly, among the designed peptides, RPPWF induces the helix conformation in Aβ42m to the maximum extent and prevents the conformational transitions in Aβ42m to aggregation-competent β-sheet structures. Furthermore, the thioflavin T (ThT) fluorescence assay depicted no self-fibrillation of RPPWF and a maximum inhibitory effect among the synthesized peptides (IC50 = 8.90 ± 0.98 μM) against Aβ42 fibrillation, consistent with the computational results. Notably, DLS and TEM analyses confirmed the RPPWF-induced modulation in Aβ42 fibrillation. RPPWF efficiently rescued PC12 cells from Aβ42 aggregate-induced neurotoxicity by notably enhancing cell viability to 89.6% as compared to 42.2% (Aβ42 alone). Remarkably, this study highlights the synergistic effect of multiple substitutions (K → R, L → P, V → P, and F → W) in the amyloidogenic KLVFF sequence of Aβ42 and depicts the importance of arginine, proline, and tryptophan residues in the RPPWF sequence in affording an efficient new potent inhibitor, RPPWF, of Aβ42 fibrillation. Furthermore, RPPWF has the potential for conjugation or further modifications to afford more effective and clinically relevant multifunctional agents against Aβ42 fibrillation in AD.
Dabas et al. (Wed,) studied this question.