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Effects of clovamide and its related compounds on the aggregations of amyloid polypeptides

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Abstract

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.

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Acknowledgements

We thank Professor Kazuhiro Irie, Associate Professor Kazuma Murakami, and Dr. Mizuho Hanaki, Graduate School of Agriculture, Kyoto University for preparing Aβ42. The analysis of clovamide and its related compounds was carried out with AVANCE-500 at Chemical Analysis Division and the Open Facility, Research Facility Center for Science and Technology, University of Tsukuba. We would like to thank Editage (www.editage.com) for English language editing. This work was partially supported by JSPS KAKENHI Grant Number JP24580156.

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Authors and Affiliations

  1. Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan

    Daigo Nomoto & Tatsuhiko Tsunoda

  2. Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan

    Hideyuki Shigemori

  3. Microbiology Research Center for Sustainability (MiCS), University of Tsukuba, Tsukuba, Ibaraki, 305-8572, Japan

    Hideyuki Shigemori

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  1. Daigo Nomoto
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  2. Tatsuhiko Tsunoda
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Correspondence to Hideyuki Shigemori.

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Nomoto, D., Tsunoda, T. & Shigemori, H. Effects of clovamide and its related compounds on the aggregations of amyloid polypeptides. J Nat Med 75, 299–307 (2021). https://doi.org/10.1007/s11418-020-01467-w

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  • DOI: https://doi.org/10.1007/s11418-020-01467-w

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