Screening and classifying small-molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry

Lydia M. Young, Janet C. Saunders, Rachel A. Mahood, Charlotte H. Revill, Richard J. Foster, Ling Hsien Tu, Daniel P. Raleigh, Sheena E. Radford, Alison E. Ashcroft

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

The search for therapeutic agents that bind specifically to precursor protein conformations and inhibit amyloid assembly is an important challenge. Identifying such inhibitors is difficult because many protein precursors of aggregation are partially folded or intrinsically disordered, which rules out structure-based design. Furthermore, inhibitors can act by a variety of mechanisms, including specific or nonspecific binding, as well as colloidal inhibition. Here we report a high-throughput method based on ion mobility spectrometry-mass spectrometry (IMS-MS) that is capable of rapidly detecting small molecules that bind to amyloid precursors, identifying the interacting protein species and defining the mode of inhibition. Using this method we have classified a variety of small molecules that are potential inhibitors of human islet amyloid polypeptide (hIAPP) aggregation or amyloid-beta 1-40 aggregation as specific, nonspecific, colloidal or non-interacting. We also demonstrate the ability of IMS-MS to screen for inhibitory small molecules in a 96-well plate format and use this to discover a new inhibitor of hIAPP amyloid assembly.

Original languageEnglish
Pages (from-to)73-81
Number of pages9
JournalNature Chemistry
Volume7
Issue number1
DOIs
Publication statusPublished - 2015 Jan 1

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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    Young, L. M., Saunders, J. C., Mahood, R. A., Revill, C. H., Foster, R. J., Tu, L. H., Raleigh, D. P., Radford, S. E., & Ashcroft, A. E. (2015). Screening and classifying small-molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. Nature Chemistry, 7(1), 73-81. https://doi.org/10.1038/nchem.2129