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

Abstract

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.

Anti-amyloidogenic Heterocyclic Peptides

“…The hydrophobic surface of the Janus cyclic peptide may protect the fibril-forming face of the amyloidogenic protein while the exposed hydrophilic surface inhibits fibril growth [98,102]. In agreement with other studies [81,106], targeting of hydrophobic interactions was shown to be an important aim for anti-amyloidogenic research.…”

“…Instead, molecular docking methods using the Aβ hairpin-stacked structure as amyloid model identified a possible site in which GS binds the Aβ fibril [130]. The structure of GS identified by crystallography [129] was shown to dock into the β-hairpin-like structure of Aβ(18-42) with its hydrophobic and hydrophilic residues interacting, respectively, with the apolar hydrophobic and polar hydrophilic interfaces within the amyloidogenic fibrillar tubes [106]. A family of mixed (αβαβα) 2 cyclopeptides was designed based on GS and shown to form β-hairpin-like structures [131] that fit the channel interface of Aβ better than GS, probably because of the increased flexibility [106].…”

“…Based on previous studies of modular β-sheets and conformational synthetic β-sheet mimics [58,72,[81][82][83]89], and using the ThT fluorescence assay and AFM, natural GS and analogs were shown to inhibit fibril formation by Aβ40 and Aβ42 [106]; however, GS was suggested not to interact with monomeric Aβ based on NMR spectroscopy. Instead, molecular docking methods using the Aβ hairpin-stacked structure as amyloid model identified a possible site in which GS binds the Aβ fibril [130].…”

“…The structure of GS identified by crystallography [129] was shown to dock into the β-hairpin-like structure of Aβ(18-42) with its hydrophobic and hydrophilic residues interacting, respectively, with the apolar hydrophobic and polar hydrophilic interfaces within the amyloidogenic fibrillar tubes [106]. A family of mixed (αβαβα) 2 cyclopeptides was designed based on GS and shown to form β-hairpin-like structures [131] that fit the channel interface of Aβ better than GS, probably because of the increased flexibility [106]. Further ThT assays and docking simulations performed on the GS derivatives illustrated the importance of hydrophilic and aromatic residues for interactions with the fibrils.…”

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

“…Although molecules such as ␤-sheet breakers (97) and cyclic peptides (98,99) have been devised to prevent amyloid aggregation, traditional antibodies have so far provided the best preliminary treatment results, at least for AD (100). It is unclear to what extent current amyloid inhibitors will block the formation of amyloid co-aggregates.…”