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A Hot‐Segment‐Based Approach for the Design of Cross‐Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self‐Assembly
Author(s) -
Andreetto Erika,
Malideli Eleni,
Yan LiMei,
Kracklauer Michael,
Farbiarz Karine,
TatarekNossol Marianna,
Rammes Gerhard,
Prade Elke,
Neumüller Tatjana,
Caporale Andrea,
Spanopoulou Anna,
Bakou Maria,
Reif Bernd,
Kapurniotu Aphrodite
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201504973
Subject(s) - amyloid (mycology) , linker , chemistry , amyloid disease , cytotoxicity , protein–protein interaction , peptide , biophysics , in vitro , biochemistry , amyloid β , amyloid fibril , microbiology and biotechnology , biology , disease , computer science , medicine , inorganic chemistry , pathology , operating system
Abstract The design of inhibitors of protein–protein interactions mediating amyloid self‐assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self‐assembly. Here we present a hot‐segment‐linking approach to design a series of mimics of the IAPP cross‐amyloid interaction surface with Aβ (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of Aβ, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self‐ and cross‐seeded IAPP self‐assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer’s disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self‐assembly and pathogenic interactions of other proteins as well.