Synthesis and mechanistic study of ultrashort peptides that inhibits Alzheimer's Aß-aggregation-induced neurotoxicity.

ABSTRACT

Misfolding/aggregation of ß-amyloid peptide lead to the formation of toxic oligomers or accumulation of amyloid plaques, which is a seminal step in the progression of Alzheimer's disease (AD). Despite continuous efforts in the development of therapeutic agents, the cure for AD remains a major challenge. Owing to specific binding affinity of structure-based peptides, we report the synthesis of new peptide-based inhibitors derived from the C-terminal sequences, Aß38-40 and Aß40-42. Preliminary screening using MTT cell viability assay and corroborative results from ThT fluorescence assay revealed a tripeptide showing significantly effective inhibition towards Aß1-42 aggregation and induced toxicity. Peptide 3 exhibited excellent cell viability of 94.3 % at 2 µM and of 100 % at 4 µM and 10 µM. CD study showed that peptide 3 restrict the conformation transition of Aß1-42 peptide towards cross-ß-sheet structure and electron microscopy validated the absence of Aß aggregates as indicated by the altered morphology of Aß1-42 in the presence of peptide 3. The HRMS-ESI, DLS and ANS studies were performed to gain mechanistic insights into the effect of inhibitor against Aß aggregation. This Aß-derived ultrashort motif provides impetus for the development of peptide-based anti-AD agents.