A Hot-Segment-Based Approach for the Design of Cross-Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self-Assembly

Angewandte Chemie
Erika AndreettoAphrodite Kapurniotu

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.

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Citations

Sep 20, 2016·Scientific Reports·Ewa A MireckaWolfgang Hoyer
Mar 9, 2017·Journal of the American Chemical Society·Sunil Kumar, Andrew D Hamilton
Mar 24, 2018·Chemical Communications : Chem Comm·Dipita BhattacharyyaAnirban Bhunia
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Aug 27, 2017·Scientific Reports·Annarita FalangaStefania Galdiero
Jun 17, 2020·Nature Structural & Molecular Biology·Qin CaoDavid S Eisenberg
Jul 8, 2017·The Journal of Biological Chemistry·Maria BakouAphrodite Kapurniotu
Sep 13, 2018·International Journal of Molecular Sciences·Sofia GiorgettiFrancesco Antonio Aprile
Feb 19, 2021·Journal of the American Chemical Society·Debabrata MaityAndrew D Hamilton
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andrea CaporaleMichele Saviano
Apr 13, 2018·Journal of the American Chemical Society·Sunil KumarAndrew D Hamilton
Oct 24, 2017·Journal of the American Chemical Society·Sunil KumarAndrew D Hamilton
Aug 28, 2021·International Journal of Molecular Sciences·Nunzianna DotiAndrea Caporale
Oct 5, 2021·Frontiers in Cell and Developmental Biology·Jacopo LesmaSandrine Ongeri

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