Journal
NATURE CHEMISTRY
Volume 7, Issue 1, Pages 73-81Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.2129
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) CASE studentship by Micromass UK Ltd/Waters Corporation [BB/I015361/1]
- BBSRC CASE studentship by Avacta Analytical [BB/H014713/1]
- BBSRC [BB/F01614X/1]
- BBSRC through Research Equipment Initiative [BB/E012558/1]
- European Research Council under European Union [322408]
- US National Institutes of Health [GM078114]
- BBSRC [BB/E012558/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1065203, BB/E012558/1, 1088554] Funding Source: researchfish
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM078114] Funding Source: NIH RePORTER
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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.
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