Author:
Ikenoue Tatsuya,Aprile Francesco A.,Sormanni Pietro,Ruggeri Francesco S.,Perni Michele,Heller Gabriella T.,Haas Christian P.,Middel Christoph,Limbocker Ryan,Mannini Benedetta,Michaels Thomas C. T.,Knowles Tuomas P. J.,Dobson Christopher M.,Vendruscolo Michele
Abstract
AbstractBicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.
Funder
Centre for Misfolding Diseases
Publisher
Springer Science and Business Media LLC
Cited by
15 articles.
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