Rationally Designed Bicyclic Peptides Prevent the Conversion of A?42 Assemblies Into Fibrillar Structures.

ABSTRACT: There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid ? peptide (A?42), 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 A?42 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 A?42 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 A?42 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.

SUBMITTER: Ikenoue T 

PROVIDER: S-EPMC7947257 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature