离子迁移光谱法
质谱成像
淀粉样蛋白(真菌学)
组合化学
生物物理学
药物发现
电喷雾
串联质谱法
离子
作者
Lydia M. Young,Janet C. Saunders,Rachel A. Mahood,Charlotte H. Revill,Richard Foster,Ling Hsien Tu,Daniel P. Raleigh,Sheena E. Radford,Alison E. Ashcroft
摘要
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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