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

Misfolding/aggregation of beta-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, A beta(38-40) and A beta(40-42). Preliminary screening using MTT cell viability assay and corroborative results from ThT fluorescence assay revealed a tripeptide showing significantly effective inhibition towards A beta(1-42) aggregation and induced toxicity. Peptide 3 exhibited excellent cell viability of 94.3 % at 2 mu M and of 100 % at 4 mu M and 10 mu M. CD study showed that peptide 3 restrict the conformation transition of A beta(1-42) peptide towards cross-beta-sheet structure and electron microscopy validated the absence of A beta aggregates as indicated by the altered morphology of A beta(1-42) 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 A beta aggregation. This A beta-derived ultrashort motif provides impetus for the development of peptide-based anti-AD agents.