Xu, Y, Maya-Martinez, R and Radford, S orcid.org/0000-0002-3079-8039 (2022) Controlling amyloid formation of intrinsically disordered proteins and peptides: Slowing down or speeding up? Essays in Biochemistry, 66 (7). pp. 959-975. ISSN 0071-1365
Abstract
The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with a range of human pathologies, including neurodegeneration, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds of millions of people worldwide, and the number of people affected is increasing sharply. However, the discovery of therapeutic agents has been immensely challenging largely because of (i) the diverse number of aggregation pathways and the multi-conformational and transient nature of the related proteins or peptides and (ii) the under-development of experimental pipelines for the identification of disease-modifying molecules and their mode-of-action. Here, we describe current approaches used in the search for small-molecule modulators able to control or arrest amyloid formation commencing from IDPs and review recently reported accelerators and inhibitors of amyloid formation for this class of proteins. We compare their targets, mode-of-action and effects on amyloid-associated cytotoxicity. Recent successes in the control of IDP-associated amyloid formation using small molecules highlight exciting possibilities for future intervention in protein-misfolding diseases, despite the challenges of targeting these highly dynamic precursors of amyloid assembly.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Author(s). This is an author produced version of an article published in Essays in Biochemistry, made available under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | accelerator, amyloid, energy landscape, inhibitor, protein aggregation, small-molecule modulator |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 204963/Z/16/Z Royal Society RSRP\R1\211057 |
Depositing User: | Symplectic Publications |
Date Deposited: | 11 Aug 2022 11:55 |
Last Modified: | 16 Dec 2023 01:13 |
Status: | Published |
Publisher: | Portland Press |
Identification Number: | 10.1042/EBC20220046 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:189828 |