A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease


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Authors
Ikenoue, Tatsuya 
Aprile, Francesco A. 
Sormanni, Pietro 
Ruggeri, Francesco S. 
Perni, Michele 
Abstract

Abstract: Bicyclic 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.

Description

Funder: Centre for Misfolding Diseases

Keywords
Article, /631/92, /631/154, article
Journal Title
Scientific Reports
Conference Name
Journal ISSN
2045-2322
Volume Title
10
Publisher
Nature Publishing Group UK