Inhibiting and reversing amyloid-β peptide (1-40) fibril formation with gramicidin S and engineered analogues.
In Alzheimer's disease, amyloid-β (Aβ) 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 Aβ peptides is likely to affect its development. ThT fluorescence measurements and AFM images showed that the natural antibiotic gramicidin S significantly inhibited Aβ amyloid formation in vitro and could dissolve amyloids that had formed in the absence of the antibiotic. In silico docking suggested that gramicidin S, a cyclic decapeptide that adopts a β-sheet conformation, binds to the Aβ peptide hairpin-stacked fibril through β-sheet interactions. This may explain why gramicidin S reduces fibril formation. Analogues of gramicidin S were also tested. An analogue with a potency that was four-times higher than that of the natural product was identified.
Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333 CC, Leiden (The Netherlands).
Jinghui
J
Luo
José M
JM
Otero
Chien-Hung
CH
Yu
Sebastian K T S
SK
Wärmländer
Astrid
A
Gräslund
Mark
M
Overhand
Jan Pieter
JP
Abrahams
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052160:Benzothiazoles; D006096:Gramicidin / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); D006096:Gramicidin; C009462:thioflavin T
Alzheimer’s disease; amyloid-beta peptides; antibiotics; fibrillization; structure-activity relationships