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-β (Aβ) peptides play a crucial role in the development of Alzheimer's disease. pEAβ_3-42 can rapidly form oligomers that gradually elongate hydrophobic segments to form β-sheet-rich amyloid intermediates, ultimately resulting in the formation of mature amyloid fibrils. pEAβ_3-42 can also catalyze the aggregation of Aβ species and subsequently accelerate the formation of amyloid senile plaques. Considering the recent clinical success of the pEAβ_3-42-targeting antibody donanemab, molecules that strongly bind pEAβ_3-42 and prevent its aggregation and catalytic effect on Aβs 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 Aβ_1-42 as previously reported, but also interacts with the hydrophobic C-terminus and middle domain of pEAβ_3-42 to maintain an unordered conformation, effectively impeding the formation of initial oligomers and subsequently halting the aggregation of pEAβ_3-42. Furthermore, TA can disrupt the “catalytic effect” of pEAβ_3-42 on amyloid aggregates, effectively suppressing Aβ aggregation and ultimately preventing the pathological events induced by Aβs.