Abstract Amyloid cascade, one of pathogenic pathways of Alzheimer’s disease (AD), was focused as one of drug discovery targets. In this study, β-secretase (BACE1) inhibitors were designed aiming at the development of multifunctional compounds targeting amyloid pathogenic cascade. Tryptophan was used as a core structure due to its properties of the central nervous system (CNS) penetration and BACE1 inhibition activity. Three amino acid residues and guanidine were selected as linkers to connect the tryptophan core structure and the extended aromatic moieties. The distance between the aromatic systems of the core structure and the extended moieties was kept at the optimal length for amyloid-β (Aβ) peptide binding to inhibit its fibrillation and aggregation. Sixteen designed compounds were evaluated in silico. Eight hit compounds of TSR and TGN series containing serine and guanidine linkers, respectively, were identified and synthesized based on docking results. TSR2 and TGN2 were found to exert strong actions as BACE1 (IC50 24.18 µM and 22.35 µM) and amyloid aggregation inhibitors (IC50 37.06 µM and 36.12 µM). Only TGN2 demonstrated a neuroprotective effect in SH-SY5Y cells by significantly reducing Aβ-induced cell death at a concentration of 2.62 µM. These results support the validity of multifunctional approaches to inhibition of the β-amyloid cascade.

中文翻译：

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对淀粉样蛋白级联抑制作用的胍基色氨酸衍生物的主要发现

摘要 淀粉样蛋白级联反应是阿尔茨海默病 (AD) 的致病途径之一，是药物发现的靶点之一。在这项研究中，β-分泌酶 (BACE1) 抑制剂的设计旨在开发针对淀粉样蛋白致病级联的多功能化合物。由于其中枢神经系统 (CNS) 渗透和 BACE1 抑制活性的特性，色氨酸被用作核心结构。选择三个氨基酸残基和胍作为连接色氨酸核心结构和扩展的芳香部分的接头。核心结构的芳香系统和扩展部分之间的距离保持在最佳长度，以便淀粉样蛋白-β (Aβ) 肽结合以抑制其纤维化和聚集。对 16 种设计的化合物进行了计算机评估。根据对接结果，鉴定并合成了分别含有丝氨酸和胍接头的 TSR 和 TGN 系列的八种命中化合物。发现 TSR2 和 TGN2 作为 BACE1 (IC50 24.18 µM 和 22.35 µM) 和淀粉样蛋白聚集抑制剂 (IC50 37.06 µM 和 36.12 µM) 发挥强大的作用。只有 TGN2 通过在 2.62 µM 的浓度下显着减少 Aβ 诱导的细胞死亡，在 SH-SY5Y 细胞中显示出神经保护作用。这些结果支持了抑制 β-淀粉样蛋白级联反应的多功能方法的有效性。只有 TGN2 通过在 2.62 µM 的浓度下显着减少 Aβ 诱导的细胞死亡，在 SH-SY5Y 细胞中显示出神经保护作用。这些结果支持了抑制 β-淀粉样蛋白级联反应的多功能方法的有效性。只有 TGN2 通过在 2.62 µM 的浓度下显着减少 Aβ 诱导的细胞死亡，在 SH-SY5Y 细胞中显示出神经保护作用。这些结果支持了抑制 β-淀粉样蛋白级联反应的多功能方法的有效性。