Abstract
Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid β (Aβ) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into β-strand conformation, which significantly improves the potency of the inhibitors against Aβ aggregation and toxicity. Furthermore, we show that by targeting different Aβ segments, the designed peptide inhibitors can selectively recognize different species of Aβ. Our study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the development of therapeutics for different amyloid-related diseases.
Highlights
Amyloid diseases, including many neurodegenerative diseases, are increasingly prevalent in aging societies (Eisenberg and Jucker, 2012; Dobson, 2017)
The 16KLVFFA21 segment has been identified as a key segment accounting for both Aβ42 and Aβ40 nucleation and fibrillation (Ahmed et al, 2010; Colletier et al, 2011; Fawzi et al, 2011; Lu et al, 2013)
The cryo-EM structure of Aβ42 fibril shows that the C-terminal segment 37GGVVIA42 plays an essential role in the fibril formation (Supplementary Figure S2). 37GGVVIA42 of one protofilament interdigitates via side chains with its counterpart of the neighboring protofilament forming a steric-zipper-like interaction to compose the mature fibril
Summary
Amyloid diseases, including many neurodegenerative diseases, are increasingly prevalent in aging societies (Eisenberg and Jucker, 2012; Dobson, 2017). Various strategies have been exploited to interfere with the process of amyloid aggregation by targeting different conformational species, including stabilizing monomers by antibodies (Ladiwala et al, 2012), redirecting monomers to nontoxic off-pathway oligomers by polyphenolic compounds (Ehrnhoefer et al, 2008), accelerating mature fibril formation by fibril binders (Bieschke et al, 2012; Jiang et al, 2013), inhibiting fibril growing by peptide blockers (Seidler et al, 2018), and disrupting amyloid assembly by nanomaterials (Hamley, 2012; Huang et al, 2014; Lee et al, 2014; Li et al, 2018; Han and He, 2018). Many of these strategies show promising inhibitory effects against toxic amyloid aggregation (Härd and Lendel, 2012; Arosio et al, 2014), but so far none has led to clinical drugs because of unsettled
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