Inhibiting and Reversing Amyloid‐β Peptide (1–40) Fibril Formation with Gramicidin S and Engineered Analogues

In Alzheimer's disease, amyloid- (A) peptides aggregate into extracellular fibrillar deposits. Although these deposits may not be the prime cause of the neurodegeneration that characterizes this disease, inhibition or dissolution of amyloid fibril formation by A peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidinS significantly inhibited A amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidinS, a cyclic decapeptide that adopts a -sheet conformation, binds to the A peptide hairpin-stacked fibril through -sheet interactions. This may explain why gramicidinS reduces fibril formation. Analogues of gramicidinS were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.