Structural and mechanistic insights into the inhibition of amyloid-ß aggregation by Aß39-42 fragment derived synthetic peptides.

ABSTRACT

The inhibition of amyloid-ß (Aß) aggregation is a promising approach towards therapeutic intervention for Alzheimer's disease (AD). Thirty eight tetrapeptides based upon Aß39-42C-terminus fragment of the parent Aß peptide were synthesized. The sequential replacement/modification employing unnatural amino acids imparted scaffold diversity, augmented activity, enhanced blood brain barrier permeability and offered proteolytic stability to the synthetic peptides. Several peptides exhibited promising protection against Aß aggregation-mediated-neurotoxicity in PC-12 cells at doses ranged between 10 µM and 0.1 µM, further confirmed by the thioflavin-T fluorescence assay. CD study illustrate that these peptides restrict the ß-sheet formation, and the non-appearance of Aß42 fibrillar structures in the electron microscopy confirm the inhibition of Aß42 aggregation. HRMS and ANS fluorescence spectroscopic analysis provided additional mechanistic insights. Two selected lead peptides 5 and 16 depicted enhanced blood-brain penetration and stability against serum and proteolytic enzyme. Structural insights into ligand-Aß interactions on the monomeric and proto-fibrillar units of Aß were computationally studied. Promising inhibitory potential and short sequence of the lead peptides offers new avenues for the advancement of peptide-derived therapeutics for AD.