海洋溴酚衍生物LXQ-5的PTP1B的结合作用和体内降糖活性研究
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摘要
二型糖尿病是一种代谢性疾病,对人类健康造成了极大的威胁。蛋白酪氨酸磷酸酶1B(PTP1B)是胰岛素信号通路中的负调控蛋白酶,是二型糖尿病治疗的重要研究靶点。本文利用酶动力学实验和分子互作技术检测了溴酚衍生物LXQ-5的PTP1B抑制作用类型和体外特异性结合作用的特点。测定糖尿病小鼠口服给药后的空腹血糖水平和血清中糖化血红蛋白以及糖化血清蛋白水平等糖尿病相关指标的变化,研究了化合物LXQ-5在小鼠体内的降糖活性。实验结果表明, LXQ-5是PTP1B的一种非竞争性抑制剂,且在体外能够与PTP1B特异性结合。LXQ-5在糖尿病小鼠体内能显著的降低空腹血糖水平和血清中糖化血红蛋白、糖化血清蛋白含量,在新型降糖药物的研发方面具有重要的研究价值。
Type 2 diabetes mellitus is a metabolic disease that poses a great threat to human health. Protein tyrosine phosphatase 1 B(PTP1 B) is a negative regulatory protease in the insulin signaling pathway and an important research target in the treatment of type 2 diabetes. In this study, enzyme kinetics experiments and molecular interaction techniques were used to determine the inhibition type and the binding characteristics of the bromophenol derivative LXQ-5 and PTP1 B. The hypoglycemic activity of LXQ-5 was also evaluated in diabetic mice, including the levels of fasting blood glucose, glycosylated hemoglobin, and glycosylated serum albumin. Results showed that LXQ-5 is a noncompetitive inhibitor of PTP1 B and capable of specifically binding to PTP1 B in vitro. LXQ-5 also significantly reduced the levels of fasting blood glucose and serum glycated hemoglobin in diabetic mice. Thus,bromophenol derivatives have great research value in the development of novel hypoglycemic drugs.
Type 2 diabetes mellitus is a metabolic disease that poses a great threat to human health. Protein tyrosine phosphatase 1 B(PTP1 B) is a negative regulatory protease in the insulin signaling pathway and an important research target in the treatment of type 2 diabetes. In this study, enzyme kinetics experiments and molecular interaction techniques were used to determine the inhibition type and the binding characteristics of the bromophenol derivative LXQ-5 and PTP1 B. The hypoglycemic activity of LXQ-5 was also evaluated in diabetic mice, including the levels of fasting blood glucose, glycosylated hemoglobin, and glycosylated serum albumin. Results showed that LXQ-5 is a noncompetitive inhibitor of PTP1 B and capable of specifically binding to PTP1 B in vitro. LXQ-5 also significantly reduced the levels of fasting blood glucose and serum glycated hemoglobin in diabetic mice. Thus,bromophenol derivatives have great research value in the development of novel hypoglycemic drugs.
引文
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[2]IDF diabetes atlas-8th edition.Available online:http://www.diabetesatlas.org/key-messages.html(accessed on18th August 2018).
[3]Smyth S,Heron A.Diabetes and obesity:the twin epidemics[J].Nature Medicine,2006,12(1):75-80.
[4]Lei L,Liu Q,Liu S,et al.Antidiabetic potential of a novel dual-target activator of glucokinase and peroxisome proliferator activated receptor-γ[J].Metabolism,2015,64(10):1250-1261.
[5]Frkic R L,He Y,Rodriguez B B,et al.Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide(INT131)Analogs for PPARγ-Targeted Antidiabetics[J].Journal of Medicinal Chemistry,2017,60(11):4584-4593.
[6]Byon J C H,Kusari A B,Kusari J.Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction[J].Molecular&Cellular Biochemistry,1998,182(1-2):101-108.
[7]Takada M,Sumi M,Maeda A,et al.Pyrroloquinoline quinone,a novel protein tyrosine phosphatase 1B inhibitor,activates insulin signaling in C2C12 myotubes and improves impaired glucose tolerance in diabetic KK-A(y)mice[J].Biochemical and Biophysical Research Communications.2012,428(2):315-320.
[8]Klaman L D,Boss O,Peroni O D,et al.Increased Energy Expenditure,Decreased Adiposity,and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase1B-Deficient Mice[J].Molecular and Cellular Biology,2000,20(15):5479-5489.
[9]Delibegovic M,Zimmer D,Kauffman C,et al.Liverspecific deletion of protein-tyrosine phosphatase 1B(PTP1B)improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress[J].Diabetes,2009,58(3):590-599.
[10]Delibegovic M,Bence K K,Mody N,et al.Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B[J].Molecular and Cellular Biology.2007,27(21):7727-7734.
[11]Woo S Y,Win N N,Wong C P,et al.Two new pyrrolo-2-aminoimidazoles from a Myanmarese marine sponge,Clathria prolifera[J].Journal of Natural Medicines,201872:803-807.
[12]Li X,Xu Q,Li C,et al.Toward a treatment of diabesity:In vitro and in vivo evaluation of uncharged bromophenol derivatives as a new series of PTP1B inhibitors[J].European Journal of Medicinal Chemistry.2019,166:178-185.
[13]Johnsson B,L?f?s S,Lindquist G.Immobilization of proteins to a carboxymethyldextran-modified gold surface for biospecific interaction analysis in surface plasmon resonance sensors[J].Analytical Biochemistry,1991,198(2):268-277.
[14]Koenig R J,Peterson C M,Jones R L,et al.Correlation of glucose regulation and hemoglobin-A-IC in diabetesmellitus[J].New England Journal of Medicine,1976,295(8):417-425.
[15]Weidner C,Wowro S J,Freiwald A,et al.Amorfrutin Bis an efficient natural peroxisome proliferator-activated receptor gamma(PPARγ)agonist with potent glucoselowering properties[J].Diabetologia,2013,56(8):1802-1812.
[16]Fukuda S,Ohta T,Sakata S,et al.Pharmacological profiles of a novel protein tyrosine phosphatase 1B inhibitor,JTT-551[J].Diabetes,Obesity and Metabolism,2010,12(4):299-306.
[17]Luo J,Xu Q,Jiang B,et al.Selectivity,cell permeability and oral availability studies of novel bromophenol derivative HPN as protein tyrosine phosphatase 1B inhibitor[J].British Journal of Pharmacology,2018,175(1):140-153.
[18]Ding H,Zhang Y,Xu C,et al.Norathyriol reverses obesity-and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B[J].Diabetologia,2014,57(10):2145-2154.