3 years ago

Selectivity, cell permeability and oral availability studies of novel bromophenol derivative HPN as PTP1B inhibitor

Lijun Wang, Dayong Shi, Xiaoling Jia, Jiao Luo, Renshuai Zhang, Xiangqian Li, Bo Jiang, Qi Xu, Ning Wu, Chuanlong Guo
Background and Purpose Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor. It is a highly validated target for type 2 diabetes therapeutics. Here, the anti-diabetic effects of HPN were evaluated in the diabetic BKS db mice. Experimental Approach The inhibitory mode of PTP1B was determined according to the Lineweaver–Burk plot in the presence of HPN. Surface plasmon resonance (SPR) assay and molecular docking were used to study the interaction between HPN and PTP1B. C2C12 skeletal muscle cells were used to investigate the cell permeability of HPN and the effect of HPN on insulin signaling pathways. Long-term effects of HPN on glycemic control were investigated in diabetic BKS db mice. Glycogen contents in liver and muscle were determined. Furthermore, the number change of β cells was evaluated by Gomori staining. Key Results HPN was identified as a specific PTP1B inhibitor. HPN directly interacted with PTP1B by binding to the catalytic domain through hydrogen bonds in a competitive mode. Approximately 56.98% of HPN entered into the cultured C2C12 myotubes. HPN ameliorated the impaired insulin signaling in palmitate-treated C2C12 myocytes. Notably, oral administration of HPN significantly protected mice from hyperglycemia, dyslipidemia and hyperinsulinemia. HPN also enhanced the storage of glycogen in liver and muscle. Moreover, HPN obviously improved the β cell numbers of the pancreatic islets. Conclusion and Implications Our results indicated that HPN is a specific PTP1B inhibitor, which exerts anti-diabetic properties with good cell permeability and oral availability.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14080

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