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

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

doi:10.3389/fnins.2021.623097

Tatsuya Ikenoue, Pietro Sormanni + Show 2 more

Open Access

https://doi.org/10.3389/fnins.2021.623097

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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.

Highlights

Since the formation of aberrant deposits composed primarily of the Aβ peptide is a molecular hallmark of Alzheimer’s disease (Selkoe and Hardy, 2016; Jack et al, 2018), a major therapeutic strategy for this condition has been based on the discovery of compounds capable of inhibiting Aβ aggregation (Schenk et al, 1999; Sevigny et al, 2016)
Bicyclic peptides have recently been introduced in the drug discovery field as they are thought to enable the combination of the advantages of small molecules with those of antibodies (Driggers et al, 2008; Getz et al, 2011; Angelini et al, 2012; Lian et al, 2014; Quartararo et al, 2014; Bartoloni et al, 2015; Bionda and Fasan, 2015)
We have described the effects on the aggregation process of Aβ42 of a panel of bicyclic peptides designed to bind different epitopes along the Aβ42 sequence

Summary

Introduction

Since the formation of aberrant deposits composed primarily of the Aβ peptide is a molecular hallmark of Alzheimer’s disease (Selkoe and Hardy, 2016; Jack et al, 2018), a major therapeutic strategy for this condition has been based on the discovery of compounds capable of inhibiting Aβ aggregation (Schenk et al, 1999; Sevigny et al, 2016). Bicyclic peptides have recently been introduced in the drug discovery field as they are thought to enable the combination of the advantages of small molecules with those of antibodies (Driggers et al, 2008; Getz et al, 2011; Angelini et al, 2012; Lian et al, 2014; Quartararo et al, 2014; Bartoloni et al, 2015; Bionda and Fasan, 2015). These molecules consist of polypeptide chains where three cysteine residues spaced within the sequence are chemically linked to a cyclic

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