Noncovalent, Electrostatic Interactions Induce Positively Cooperative Binding of Small Molecules to Alzheimer's and Parkinson's Disease-Related Amyloids
Noncovalent, Electrostatic Interactions Induce Positively Cooperative Binding of Small Molecules to Alzheimer's and Parkinson's Disease-Related Amyloids
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DOI：
10.1021/acschemneuro.8b00280
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发表时间：
2019-02-01
影响因子：
5
通讯作者：
Yang, Jerry
中科院分区：
文献类型：
--
作者：
Cifelli, Jessica L.;Capule, Christina C.;Yang, Jerry
淀粉样蛋白是自组装的蛋白质聚集体，是许多神经系统疾病的主要标志。淀粉样蛋白的共同特征之一是存在高密度的小分子配体的多个结合位点，使其成为设计多聚体结合剂的一个有吸引力的目标。在这里，我们证明了反向带电的苯并噻唑分子的1:1混合物之间的非共价分子间相互作用增强了它们与两种不同淀粉样蛋白聚集体的结合：阿尔茨海默病相关的淀粉样蛋白- β (a β)肽或帕金森病相关的α -突触核蛋白（α S）蛋白。我们发现这种混合物导致淀粉样蛋白目标的正合作结合，与不带电的母体化合物相比，结合能力增强了10倍。使用非共价相互作用观察到的淀粉样蛋白结合的增强程度与苯并噻唑二聚体聚集a β的程度相似。这些结果代表了一种设计具有增强亲和力的淀粉样蛋白靶向分子的新策略，这可能有助于开发新的淀粉样蛋白相关疾病的诊断或治疗策略。
Amyloids are self-assembled protein aggregates that represent a major hallmark of many neurologic and systemic diseases. Among the common features of amyloids is the presence of a high density of multiple binding sites for small molecule ligands, making them an attractive target for design of multimeric binding agents. Here, we demonstrate that noncovalent, intermolecular interactions between a 1:1 mixture of oppositely charged benzothiazole molecules enhances their binding to two different amyloid aggregates: Alzheimer's-related amyloid-beta (A beta) peptides or Parkinson's-related alpha-synuclein (alpha S) proteins. We show that this mixture leads to positively cooperative binding to amyloid targets, with up to 10-fold enhancement of binding compared to the uncharged parent compound. The observed enhancement of amyloid binding using noncovalent interactions was similar in magnitude to a benzothiazole dimer to aggregated A beta. These results represent a novel strategy for designing amyloid-targeting molecules with enhanced affinity, which could aid in the development of new diagnostic or treatment strategies for amyloid-associated diseases.