Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Bioorg Med Chem. 2011 Sep 1;19(17):5147-54. doi: 10.1016/j.bmc.2011.07.016. Epub 2011 Jul 19.
Whole brain imaging of tau-bearing neurofibrillary lesions has the potential to improve the premortem diagnosis and staging of Alzheimer's disease. Diverse compounds with high affinity for tau aggregates have been reported from high-throughput screens, but the affinity driving features common among them have not been determined. To identify these features, analogs of compounds discovered by high-throughput screening, including phenothiazine, triarylmethine, benzothiazole, and oxindole derivatives, were tested for their ability to displace fluorescent thioflavin dyes from filaments made from recombinant tau protein or authentic paired helical filaments purified from Alzheimer's disease tissue. When representative members of all scaffolds were assayed, the rank order of binding affinity determined for synthetic and authentic filaments correlated strongly, indicating that synthetic filaments have predictive utility for ligand development. Within individual scaffold families, binding affinity was found to correlate with compound polarizability, consistent with a role for dispersion forces in mediating ligand binding. Overall, the data indicate that polarizability is an important commonality among structurally diverse tau binding ligands, and that affinity for tau aggregates can be maximized by integrating formal assessment of this parameter into ligand discovery efforts.
对携带 tau 蛋白的神经纤维缠结进行全脑成像，有可能提高阿尔茨海默病的生前诊断和分期水平。从高通量筛选中已经报道了许多对 tau 聚集物具有高亲和力的化合物，但尚未确定它们之间共有的亲和力驱动特征。为了确定这些特征，我们测试了通过高通量筛选发现的化合物的类似物，包括吩噻嗪、三芳基甲川、苯并噻唑和吲哚衍生物，以检测它们从重组 tau 蛋白或从阿尔茨海默病组织中纯化的真实双螺旋丝形成的纤维中置换荧光硫黄素染料的能力。当对所有支架的代表性成员进行检测时，确定的合成和真实纤维的结合亲和力的排序与相关性很强，表明合成纤维对配体开发具有预测作用。在单个支架家族内，发现结合亲和力与化合物极化率相关，这与分散力在介导配体结合中的作用一致。总的来说，这些数据表明，极化率是结构多样的 tau 结合配体之间的一个重要共性，并且通过将对该参数的正式评估纳入配体发现工作中，可以最大限度地提高对 tau 聚集物的亲和力。
