The formation and accumulation of amyloid aggregates are the phenomena that accompany amyloidoses, which are currently untreatable and include Alzheimer's and Parkinson's diseases, diabetes mellitus, non-neuropathic lysozyme systemic amyloidosis, and others. One of the very promising therapeutic approaches seems to be an inhibition of amyloid formation and/or clearance of amyloid aggregates. Small molecules have a great potential to interfere with amyloid fibrillation of peptides and polypeptides, which can be improved by connection of cyclic structures into single multicyclic molecules and their dimerization. In our study, we focused on heterodimers consisting of 7-methoxytacrine (7-MEOTA) and 2-aminobenzothiazole (BTZ) parent molecules connected by an aliphatic linker. Using in vitro and in silico methods, we investigated the ability of studied compounds to inhibit the amyloid aggregation of hen egg white lysozyme. Heterodimerization led to significant improvement of inhibitory activity compared to that of the parent molecules. The efficiency of the heterodimers varied; the most effective inhibitor contained the longest linker, eight carbons long. We suggest that binding of a heterodimer to a lysozyme blocks the interaction between the β-domain and C-helix region essential for the formation of amyloid cross-β structure. Elongation of the linker ultimately enhances the compound's ability to prevent this interaction by allowing the BTZ part of the heterodimer to bind more effectively, increasing the compound's binding affinity, and also by greater steric obstruction. This study represents an important contribution to the recent rational design of potential lead small molecules with anti-amyloid properties, and the heterodimers studied are prospective candidates for the treatment of systemic lysozyme amyloidosis and other amyloid-related diseases.

中文翻译：

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7-甲氧基他克林和2-氨基苯并噻唑异二聚体：基于合理设计的淀粉样抑制剂的结构-机理关系。

淀粉样蛋白聚集体的形成和积累是淀粉样蛋白伴随的现象，淀粉样蛋白目前无法治疗，包括阿尔茨海默氏病和帕金森氏病，糖尿病，非神经性溶菌酶系统性淀粉样变性病等。一种非常有前途的治疗方法似乎是抑制淀粉样蛋白的形成和/或清除淀粉样蛋白聚集体。小分子具有很大的潜力干扰肽和多肽的淀粉样原纤维化，这可以通过将环状结构连接成单个多环分子并将其二聚化来改善。在我们的研究中，我们专注于由脂肪族接头连接的7-甲氧基他克林（7-MEOTA）和2-氨基苯并噻唑（BTZ）母体分子组成的异二聚体。使用体外和计算机模拟方法，我们研究了所研究化合物抑制鸡蛋清溶菌酶淀粉样蛋白聚集的能力。与母体分子相比，异二聚作用导致抑制活性的显着改善。异二聚体的效率各不相同；最有效的抑制剂包含最长的连接子，长度为8个碳。我们建议异源二聚体与溶菌酶的结合会阻止β结构域和C螺旋区之间的相互作用，这对于形成淀粉样蛋白跨β结构至关重要。连接子的延长通过允许异二聚体的BTZ部分更有效地结合，增加了化合物的结合亲和力以及更大的空间阻塞，最终增强了该化合物防止这种相互作用的能力。