Modulation and detection of tau aggregation with small-molecule ligands.
Modulation and detection of tau aggregation with small-molecule ligands.
复制标题
用小分子配体调节和检测tau聚集。
DOI：
10.2174/156720509789207976
复制
发表时间：
2009-10
影响因子：
2.1
通讯作者：
Kuret J
中科院分区：
文献类型：
--
作者：
Chang E;Honson NS;Bandyopadhyay B;Funk KE;Jensen JR;Kim S;Naphade S;Kuret J
高通量和其他筛选方法的最新结果表明，小分子可以以三种不同的模式与重组全长tau单体和纤维状tau聚集体直接相互作用。首先，在高浓度方案（>10微摩尔）中，某些阴离子分子如刚果红通过涉及二聚核和单体介导的延伸的成核-延伸机制有效地促进tau细丝形成。这些化合物可用于体外和生物模型中的tau聚集建模。第二，在低浓度方案（<1微摩尔）中，其它配体，包括花青染料，显示聚集拮抗剂活性。可以预防或逆转纤维化的化合物是疾病病理学的候选修饰剂。最后，某些化合物在多个结合位点以不同的亲和力结合成熟的tau原纤维，而不调节聚集反应。对于一些配体，可以在结合亲和力水平证明tau聚集体相对于由β-淀粉样蛋白或α-突触核蛋白组成的细丝的>10倍选择性。总之，这些观察结果表明，小分子具有询问tau聚集途径，抑制神经炎性病变形成，并通过全脑成像的神经系统病变的选择性尸检前检测的效用。
Recent results from high-throughput and other screening approaches reveal that small molecules can directly interact with recombinant full-length tau monomers and fibrillar tau aggregates in three distinct modes. First, in the high concentration regime (>10 micromolar), certain anionic molecules such as Congo red efficiently promote tau filament formation through a nucleation-elongation mechanism involving a dimeric nucleus and monomer-mediated elongation. These compounds are useful for modeling tau aggregation in vitro and in biological models. Second, in the low concentration regime (<1 micromolar), other ligands, including cyanine dyes, display aggregation antagonist activity. Compounds that can prevent or reverse fibrillization are candidate modifiers of disease pathology. Finally, certain compounds bind mature tau fibrils with varying affinities at multiple binding sites without modulating the aggregation reaction. For some ligands, >10-fold selectivity for tau aggregates relative to filaments composed of beta-amyloid or alpha-synuclein can be demonstrated at the level of binding affinity. Together these observations suggest that small-molecules have utility for interrogating the tau aggregation pathway, for inhibiting neuritic lesion formation, and for selective pre-mortem detection of neurofibrillary lesions through whole brain imaging.
登录
查看更多内容
DOI：
10.1016/j.bbrc.2007.03.056
发表时间：
2007-06-22
影响因子：
3.1
作者：
Crowe, Alex;Ballatore, Carlo;Lee, Virginia M. -Y.
通讯作者：
Lee, Virginia M. -Y.
影响因子：
4.7
作者：
Chang, Edward;Kim, Sohee;Yin, Haishan;Nagaraja, Haikady N.;Kuret, Jeff
通讯作者：
Kuret, Jeff
DOI：
10.1016/j.bbrc.2007.08.166
发表时间：
2007-11-09
影响因子：
3.1
作者：
Honson, Nicolette S.;Jensen, Jordan R.;Kuret, Jeff
通讯作者：
Kuret, Jeff
影响因子：
16.6
作者：
Bulic, Bruno;Pickhardt, Marcus;Waldmann, Herbert
通讯作者：
Waldmann, Herbert
影响因子：
4.8
作者：
Chirita, CN;Necula, M;Kuret, J
通讯作者：
Kuret, J