Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance.
Bioorg Chem
; 90: 103087, 2019 09.
Article
em En
| MEDLINE
| ID: mdl-31284101
ABSTRACT
Natural products as antidiabetic agents have been shown to stimulate insulin signaling via the inhibition of the protein tyrosine phosphatases relevant to insulin resistance. Previously, we have identified PTPN9 and DUSP9 as potential antidiabetic targets and a multi-targeting natural product thereof. In this study, knockdown of PTPN11 increased AMPK phosphorylation in differentiated C2C12 muscle cells by 3.8 fold, indicating that PTPN11 could be an antidiabetic target. Screening of a library of 658 natural products against PTPN9, DUSP9, or PTPN11 identified chebulinic acid (CA) as a strong allosteric inhibitor with a slow cooperative binding to PTPN9 (IC50â¯=â¯34â¯nM) and PTPN11 (IC50â¯=â¯37â¯nM), suggesting that it would be a potential antidiabetic candidate. Furthermore, CA stimulated glucose uptake and resulted in increased AMP-activated protein kinase (AMPK) phosphorylation. Taken together, we demonstrated that CA increased glucose uptake as a dual inhibitor of PTPN9 and PTPN11 through activation of the AMPK signaling pathway. These results strongly suggest that CA could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Taninos Hidrolisáveis
/
Diabetes Mellitus Tipo 2
/
Proteínas Tirosina Fosfatases não Receptoras
/
Proteína Tirosina Fosfatase não Receptora Tipo 11
/
Hipoglicemiantes
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article