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

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 amyloi...

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Published in:	Journal of natural medicines Vol. 75; no. 2; pp. 299 - 307
Main Authors:	Nomoto, Daigo, Tsunoda, Tatsuhiko, Shigemori, Hideyuki
Format:	Journal Article
Language:	English
Published:	Singapore Springer Singapore 01-03-2021 Springer Nature B.V
Subjects:	Alzheimer's disease Amylin Amyloid beta-Peptides - drug effects Biomedical and Life Sciences Biomedicine Catechol Complementary & Alternative Medicine Diabetes Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - drug therapy Disaggregation Flowers & plants Humans Medicinal Chemistry Neurodegenerative diseases Original Paper Pancreas Pharmacology/Toxicology Pharmacy Phytochemicals Plant Sciences Polypeptides Structure-Activity Relationship Tyrosine - analogs & derivatives Tyrosine - pharmacology Tyrosine - therapeutic use Type 2 diabetes Alzheimer’s disease Human islet amyloid polypeptide Amyloid β Catechol Structure–activity relationship Clovamide
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Summary:	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.
ISSN:	1340-3443 1861-0293
DOI:	10.1007/s11418-020-01467-w