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Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

Published version
Peer-reviewed

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Authors

Ikenoue, Tatsuya 
Aprile, Francesco A. 
Sormanni, Pietro 
Vendruscolo, Michele 

Abstract

There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.

Description

Keywords

Neuroscience, amyloid—beta, Alzheimer’s disease, bicyclic peptides, rational design, protein aggregation

Journal Title

Frontiers in Neuroscience

Conference Name

Journal ISSN

1662-453X

Volume Title

15

Publisher

Frontiers Media S.A.