Rationally designed bicyclic peptides prevent the conversion of A beta 42 assemblies into fibrillar structures
Author(s)
Ikenoue, Tatsuya
Aprile, Francesco A
Sormanni, Pietro
Vendruscolo, Michele
Type
Journal Article
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.
Date Issued
2021-02-25
Date Acceptance
2021-02-01
Citation
Frontiers in Neuroscience, 2021, 15, pp.1-9
ISSN
1662-453X
Publisher
Frontiers Media
Start Page
1
End Page
9
Journal / Book Title
Frontiers in Neuroscience
Volume
15
Copyright Statement
© 2021 Ikenoue, Aprile, Sormanni and Vendruscolo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Sponsor
Medical Research Council (MRC)
Alzheimer's Society
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000627356600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
MR/S033947/1
511
Subjects
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
amyloid—
beta
Alzheimer’
s disease
bicyclic peptides
rational design
protein aggregation
Publication Status
Published
Article Number
ARTN 623097
Date Publish Online
2021-02-25