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Ruthenium(III) complexes with imidazole ligands that modulate the aggregation of the amyloid-β peptide via hydrophobic interactions
Journal of Inorganic Biochemistry ( IF 3.9 ) Pub Date : 2020-11-02 , DOI: 10.1016/j.jinorgbio.2020.111303
Gideon K Yawson 1 , Samantha E Huffman 1 , Samuel S Fisher 1 , Paige J Bothwell 2 , David C Platt 1 , Marjorie A Jones 1 , Gregory M Ferrence 1 , Christopher G Hamaker 1 , Michael I Webb 1
Affiliation  

Alzheimer's disease (AD) is the most common form of dementia, characterized by extracellular protein deposits, comprised primarily of the peptide amyloid-beta (Aβ), are a pathological indicator of the disease. Commonly known as Aβ plaques, these deposits contain a relatively high concentration of metals, making metallotherapeutics uniquely suited to target soluble Aβ, thereby limiting its aggregation and cytotoxicity. Ruthenium-based complexes are promising candidates for advancement, as the complex PMRU20 (2-aminothiazolium [trans-RuCl4(2-aminothiazole)2]) and several thiazole-based derivatives were found to prevent the aggregation of Aβ, with hydrogen-bonding functional groups improving their performance. Further investigation into the impact of the heteroatom in the azole ring on the activity of Ru complexes was achieved through the synthesis and evaluation of a small set of imidazole-based compounds. The ability of the complexes to prevent the aggregation of Aβ was determined where the same sample was subjected to analysis by three complementary methods: ThT fluorescence, dynamic light scattering (DLS), and transmission electron microscopy (TEM). It was found that hydrophobic interactions, along with hydrogen-bonding via the imidazole nitrogen heteroatom, promoted interactions with the Aβ peptide, thereby limiting its aggregation. Furthermore, it was found that having rapid and sequential exchange proved detrimental as it resulted in a decreased association with Aβ. These results highlight important considerations between a balance of intermolecular interactions and ligand exchange kinetics in the design of further therapeutic candidates.



中文翻译:

钌 (III) 与咪唑配体形成复合物,通过疏水相互作用调节淀粉样蛋白-β 肽的聚集

阿尔茨海默病 (AD) 是最常见的痴呆症形式,其特征是细胞外蛋白质沉积,主要由肽淀粉样蛋白-β (Aβ) 组成,是该疾病的病理指标。通常称为 Aβ 斑块,这些沉积物含有相对高浓度的金属,使金属治疗剂特别适合靶向可溶性 Aβ,从而限制其聚集和细胞毒性。钌基复合物是有前景的候选物,因为复合物 PMRU20(2-氨基噻唑鎓[反式-RuCl 4(2-氨基噻唑)2]) 和几种基于噻唑的衍生物被发现可以防止 Aβ 的聚集,氢键官能团提高了它们的性能。通过合成和评估一小组基于咪唑的化合物,进一步研究了唑环中的杂原子对 Ru 配合物活性的影响。复合物防止 Aβ 聚集的能力是通过三种互补方法对同一样品进行分析来确定的:ThT 荧光、动态光散射 (DLS) 和透射电子显微镜 (TEM)。发现疏水相互作用以及通过咪唑氮杂原子的氢键促进与 Aβ 肽的相互作用,从而限制其聚集。此外,结果表明,快速和顺序交换被证明是有害的,因为它会导致与 Aβ 的关联减少。这些结果突出了在设计其他治疗候选药物时平衡分子间相互作用和配体交换动力学之间的重要考虑因素。

更新日期:2020-11-09
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