Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
J Nat Med. 2021 Mar;75(2):299-307. doi: 10.1007/s11418-020-01467-w. Epub 2021 Jan 3.
Alzheimer's disease (AD) and type 2 diabetes (T2D) are common diseases in the elderly, and the increasing number of patients with these diseases has become a serious health problem worldwide. The aggregation and development of plaque of amyloid polypeptides (amyloid β; Aβ and human islet amyloid polypeptide; hIAPP, amylin) are found in the brains of patients with AD and the pancreas of patients with T2D and are considered to be, in part, the causes of both diseases, respectively. Therefore, preventing amyloid aggregation may be a promising therapeutic strategy for preventing AD and T2D. In addition, the disaggregation of the already aggregated amyloid polypeptides is expected to contribute to the prevention and treatment of both diseases as amyloid polypeptide aggregations begin several decades before the onset of disease. Therefore, in this study, we investigated the hIAPP aggregation inhibitory activity and Aβ42/hIAPP disaggregation activity of clovamide which had shown inhibitory activity against Aβ42 aggregation in our previous studies. In addition, active sites were identified (structure-activity relationship analysis) using clovamide-related compounds in which hydroxyl groups of these compounds were either eliminated or methylated. Our results showed that the compounds with one or two catechol moieties showed strong hIAPP aggregation inhibitory activity and Aβ42/hIAPP disaggregation activity; and the non-catechol type compounds showed little or no activity. This suggests that the catechol moiety is important in amyloid polypeptide aggregation inhibition and disaggregation. Thus, clovamide and its related compounds may be promising therapeutic strategies for inhibiting amyloid polypeptide-related pathology in AD and T2D.
阿尔茨海默病（AD）和 2 型糖尿病（T2D）是老年人常见的疾病，这些疾病患者数量的增加已成为全球严重的健康问题。在 AD 患者的大脑和 T2D 患者的胰腺中发现淀粉样多肽（淀粉样 β；Aβ和人胰岛淀粉样多肽；hIAPP，胰岛淀粉样肽）的斑块聚集和发展，分别被认为是这两种疾病的部分原因。因此，预防淀粉样蛋白聚集可能是预防 AD 和 T2D 的一种有前途的治疗策略。此外，已经聚集的淀粉样多肽的解聚有望为这两种疾病的预防和治疗做出贡献，因为淀粉样多肽聚集在疾病发作前几十年就开始了。因此，在这项研究中，我们研究了在我们之前的研究中显示出对 Aβ42 聚集有抑制活性的稠李酰胺对 hIAPP 聚集的抑制活性和 Aβ42/hIAPP 的解聚活性。此外，还使用这些化合物中羟基被消除或甲基化的稠李酰胺相关化合物进行了活性部位鉴定（构效关系分析）。研究结果表明，具有一个或两个儿茶酚结构部分的化合物表现出强烈的 hIAPP 聚集抑制活性和 Aβ42/hIAPP 的解聚活性；而非儿茶酚型化合物则显示出很少或没有活性。这表明儿茶酚结构部分对于淀粉样多肽聚集的抑制和解聚很重要。因此，稠李酰胺及其相关化合物可能是抑制 AD 和 T2D 中与淀粉样多肽相关的病理学的有前途的治疗策略。
