Controlling amyloid formation of intrinsically disordered proteins and peptides: slowing down or speeding up?

The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amy-loid fibrils is associated with a range of human pathologies, including neurodegenera-tion, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds of millions of people worldwide, and the number of people affected is in-creasing 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 commenc-ing from IDPs and review recently reported accelerators and inhibitors of amyloid forma-tion 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 amy-loid formation using small molecules highlight exciting possibilities for future intervention in protein-misfolding diseases, despite the challenges of targeting these highly dynamic pre-cursors of amyloid assembly.

Automated summary

The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with various human pathologies. Discovering therapeutic agents for these diseases is challenging due to the diverse aggregation pathways and transient nature of IDPs.