期刊
CURRENT ALZHEIMER RESEARCH
卷 12, 期 9, 页码 814-828出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/156720501209151019104951
关键词
Alzheimer's disease; drug discovery; high throughput screening; inhibitor; protein aggregation; tau; taupathies; therapeutic
资金
- Wellcome Trust (UK)
- Medical Research Council (UK)
- Elan Pharmaceuticals (USA)
- Canadian Institutes of Health Research (Canada)
- Alzheimer Society of Ontario (Canada)
- Hungarian Brain Research Program [KTIA_NAP_13-2014-0009]
- DZNE
- MPG
- MRC [MC_G1000734] Funding Source: UKRI
A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer's and Parkinson's diseases.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据