Small molecule probes of protein aggregation

• Published in: Current opinion in chemical biology Vol. 39; pp. 90 - 99
• Main Authors: Young, Lydia M, Ashcroft, Alison E, Radford, Sheena E
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2017
• Subjects: Animals; Drug Discovery; Humans; Molecular Probes - metabolism; Protein Aggregates; Proteins - chemistry; Proteins - metabolism; Small Molecule Libraries - metabolism
• ISSN: 1367-5931; 1879-0402
• DOI: 10.1016/j.cbpa.2017.06.008

[Display omitted] •A range of functionally and structurally unrelated proteins form amyloid.•Toxic intermediates remain elusive, making their targeting a significant challenge.•Design and screening strategies have been devised for amyloid inhibitor discovery.•Small molecules show promise as inhibitors of amyloid formation and its associated toxicity.•Mass spectrometry and kinetic analyses enable identification of the mechanism of amyloid inhibition. Understanding the mechanisms of amyloid formation and toxicity remain major challenges. Although substantial progress has been made in the development of methods able to identify the species formed during self-assembly and to describe the kinetic mechanisms of aggregation, the structure(s) of non-native species, including potentially toxic oligomers, remain elusive. Moreover, how fibrils contribute to disease remains unclear. Here we review recent advances in the development of small molecules and other reagents that are helping to define the mechanisms of protein aggregation in molecular detail. Such probes form a powerful platform with which to better define the mechanisms of structural conversion into amyloid fibrils and may provide the much-needed stepping stone for future development of successful therapeutic agents.