title: Trivaric acid, a new inhibitor of PTP1b with potent beneficial effect on diabetes.
abstract: OBJECTIVE
  To screen a potential PTP1b inhibitor from the microbial origin-based compound library and to investigate the potential anti-diabetic effects of the inhibitor in vivo and determine its primary anti-diabetic mechanism in vitro and in silico.
  
  
  METHODS
  PTP1b inhibitory activity was measured using recombination protein as the enzyme and p-NPP as the substrate. The binding of the inhibitor to PTP1b was analysed by docking in silico and confirmed by ITC experiments. The intracellular signalling pathway was detected by Western blot analysis in HepG2 cells. The anti-diabetic effects were evaluated using a diabetic mice model in vivo.
  
  
  RESULTS
  Among 545 microbial origin-based pure compounds tested, trivaric acid, a tridepside, was selected as a PTP1B inhibitor exhibiting strong inhibitory activity with an IC50of 173nM. Docking and ITC studies showed that trivaric acid was able to spontaneously bind to PTP1b and may inhibit PTP1b by blocking the catalytic domain of the phosphatase. Trivaric acid also enhanced the ability of insulin to stimulate the IR/IRS/Akt/GLUT2 pathway and increase the glucose consumption in HepG2 cells. In diabetic mice, trivaric acid that had been encapsulated into Eudrgit L100-5.5 showed significant anti-diabetic effects, improving insulin resistance, leptin resistance and lipid profile and weight control at doses of 5mg/kg and 50mg/kg.
  
  
  CONCLUSIONS
  Trivaric acid is a potential lead compound in the search for anti-diabetic agents targeting PTP1b.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Sun
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China.
authors.forename: Bowei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: New Drug Research and Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering and Research Center, Shijiazhuang 050015, China.
authors.forename: Haizhou
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Zhuang
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: New Drug Research and Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering and Research Center, Shijiazhuang 050015, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Lu
authors.affiliation: Key Laboratory of Biotechnology and Bioresources Utilization, Dalian Minzu University, Dalian 116024, Liaoning, China.
authors.forename: Chunshan
authors.initials: C
authors.lastname: Quan
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China. Electronic address: yshdong@dlut.edu.cn.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Dong
authors.affiliation: New Drug Research and Development Center, North China Pharmaceutical Group Corporation, National Microbial Medicine Engineering and Research Center, Shijiazhuang 050015, China. Electronic address: anzhengzhihui@hotmail.com.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, Liaoning, China.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Xiu
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D053630:Depsides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000180:Acrylic Resins; D001786:Blood Glucose; D053630:Depsides; D004337:Drug Carriers; D004791:Enzyme Inhibitors; C446821:Eudragit L100-55; D007004:Hypoglycemic Agents; D007328:Insulin; C581105:trivaric acid; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: Diabetes; Insulin sensitivity; Insulin signalling pathway; Protein tyrosine phosphatase 1b; Trivaric acid