Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2′,3,3′-Tetrabromo-4,4′,5,5′-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice

• Published in: Molecular pharmaceutics Vol. 16; no. 5; pp. 1839 - 1850
• Main Authors: Li, Chao, Luo, Jiao, Guo, Shuju, Jia, Xiaoling, Guo, Chuanlong, Li, Xiangqian, Xu, Qi, Shi, Dayong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.05.2019
• Subjects: Administration, Oral; Animals; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Catalytic Domain; Cell Line; Diabetes Mellitus, Type 2 - drug therapy; Glycogen - metabolism; Hydrogen Bonding; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Inhibitory Concentration 50; Insulin - metabolism; Insulin Resistance; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Molecular Docking Simulation; Myoblasts - drug effects; Myoblasts - metabolism; Plant Extracts - administration & dosage; Plant Extracts - chemistry; Plant Extracts - pharmacology; Plant Extracts - therapeutic use; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - antagonists & inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - isolation & purification; Rhodophyta - chemistry; Signal Transduction - drug effects; type 2 diabetes mellitus; hypoglycemic activity; protein tyrosine phosphatase 1B; dyslipidemia; insulin resistance
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.8b01106

Protein tyrosine phosphatase 1B (PTP1B) is a widely confirmed target of the type 2 diabetes mellitus (T2DM) treatment. Herein, we reported a highly specific PTP1B inhibitor 2,2′,3,3′-tetrabromo-4,4′,5,5′-tetrahydroxydiphenylmethane (compound 1), which showed promising hypoglycemic activity in diabetic BKS db mice. With the IC50 value of 2.4 μM, compound 1 could directly bind to the catalytic pocket of PTP1B through a series of hydrogen bonds. Surface plasmon resonance analysis revealed that the target affinity [KD (equilibrium dissociation constant) value] of compound 1 binding to PTP1B was 2.90 μM. Moreover, compound 1 could activate the insulin signaling pathway in C2C12 skeletal muscle cells. We further evaluated the long-term effects of compound 1 in diabetic BKS db mice. Notably, oral administration of compound 1 significantly reduced the blood glucose levels of diabetic mice with increasing insulin sensitivity. In addition, the dyslipidemia of diabetic mice was also significantly improved by compound 1 gavage. The histological experiments showed that compound 1 treatment significantly ameliorated the disordered hepatic and pancreatic architecture and increased the glycogen content in the liver tissues as well as improved the insulin secretion function of pancreas. Taken together, our results manifested that the natural product compound 1 was a highly specific PTP1B inhibitor, which could activate insulin signaling pathway and ameliorate hyperglycemia and dyslipidemia in diabetic BKS db mice.