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.