A rationally designed bicyclic peptide remodels A?42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer's disease.

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 ? peptide (A?42), 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 A?42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing A?42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

SUBMITTER: Ikenoue T 

PROVIDER: S-EPMC7498612 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature