School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.
Department of Chemistry, Dongguk University, Seoul 100-715, Republic of Korea.
Bioorg Chem. 2019 Sep;90:103087. doi: 10.1016/j.bioorg.2019.103087. Epub 2019 Jul 2.
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 (IC = 34 nM) and PTPN11 (IC = 37 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.
天然产物作为抗糖尿病药物已被证明通过抑制与胰岛素抵抗相关的蛋白酪氨酸磷酸酶来刺激胰岛素信号。先前，我们已经确定 PTPN9 和 DUSP9 为潜在的抗糖尿病靶标及其多靶向天然产物。在这项研究中，PTPN11 的敲低使分化的 C2C12 肌肉细胞中的 AMPK 磷酸化增加了 3.8 倍，表明 PTPN11 可能是抗糖尿病靶标。针对 PTPN9、DUSP9 或 PTPN11 的 658 种天然产物文库的筛选鉴定出诃子酸 (CA) 是一种强的变构抑制剂，对 PTPN9（IC=34 nM）和 PTPN11（IC=37 nM）具有缓慢的协同结合作用，提示其可能是一种潜在的抗糖尿病候选物。此外，CA 刺激葡萄糖摄取并导致 AMP 激活的蛋白激酶 (AMPK) 磷酸化增加。综上所述，我们证明 CA 通过激活 AMPK 信号通路作为 PTPN9 和 PTPN11 的双重抑制剂增加葡萄糖摄取。这些结果强烈表明 CA 可作为治疗 2 型糖尿病的潜在治疗候选物。
