摘要
减轻固有无序化蛋白(IDP)聚集的可能方法是通过与小分子的结合保持蛋白的自然功能状态。但是,通过小分子对IDP自然状态的靶向会因其多种异构构象而变得困难。对此,我们用高通量化学微阵列表面等离子体共振成像筛选检测小分子与全长Tau的结合。全长Tau是与一系列Tau病变的发作有关的蛋白。该筛选鉴定了一批结合在Tau上的新的类药片断和类前体化合物。我们证实这些命中化合物能减轻不同Tau构造在体外和N2a细胞中的聚集。该结果证明Tau是类药小分子的有活性的受体。我们提出的药物发现方法可应用于与其它错折叠疾病(如老年痴呆和帕金森病)有关的其它IDP。
关键词: 老年痴呆,药物发现,高通量筛选,抑制剂,蛋白质聚集,tau,tau病变,治疗。
Current Alzheimer Research
Title:Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies
Volume: 12 Issue: 9
Author(s): Marcus Pickhardt, Thomas Neumann, Daniel Schwizer, Kari Callaway, Michele Vendruscolo, Dale Schenk, Peter St. George-Hyslop, Eva M. Mandelkow, Christopher M. Dobson and Lisa McConlogue, Eckhard Mandelkow and Gergely Toth
Affiliation:
关键词: 老年痴呆,药物发现,高通量筛选,抑制剂,蛋白质聚集,tau,tau病变,治疗。
摘要: 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.
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Marcus Pickhardt, Thomas Neumann, Daniel Schwizer, Kari Callaway, Michele Vendruscolo , Dale Schenk, Peter St. George-Hyslop, Eva M. Mandelkow, Christopher M. Dobson and Lisa McConlogue, Eckhard Mandelkow and Gergely Toth , Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies, Current Alzheimer Research 2015; 12 (9) . https://dx.doi.org/10.2174/156720501209151019104951
DOI https://dx.doi.org/10.2174/156720501209151019104951 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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