Targeting the hydrophobic region of pyroglutamate-modified amyloid-β by tyrocidine A prevents its nucleation-aggregation process and its "catalytic effect" on the Aβs aggregation

Pyroglutamate (pE)-modified amyloid-beta (A beta) peptides play a crucial role in the development of Alzheimer's disease. pEA beta(3-42) can rapidly form oligomers that gradually elongate hydrophobic segments to form beta-sheet-rich amyloid intermediates, ultimately resulting in the formation of mature amyloid fibrils. pEA beta(3-42) can also catalyze the aggregation of A beta species and subsequently accelerate the formation of amyloid senile plaques. Considering the recent clinical success of the pEA beta(3-42)-targeting antibody donanemab, molecules that strongly bind pEA beta(3-42) and prevent its aggregation and catalytic effect on A beta s may also provide potential therapeutic options for Alzheimer's disease. Here, we demonstrate that the natural antibiotic cyclopeptide tyrocidine A (TA) not only strongly inhibits the aggregation of A beta(1-42) as previously reported, but also interacts with the hydrophobic C-terminus and middle domain of pEA beta(3-42) to maintain an unordered conformation, effectively impeding the formation of initial oligomers and subsequently halting the aggregation of pEA beta(3-42). Furthermore, TA can disrupt the "catalytic effect" of pEA beta(3-42) on amyloid aggregates, effectively suppressing A beta aggregation and ultimately preventing the pathological events induced by A beta s.