CN102670582A - 芒果苷元对ptp1b的抑制活性及其应用 - Google Patents
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Abstract
芒果苷元对PTP1B的抑制活性及其应用。本发明属于生物制药技术领域，具体涉及一种四羟基
酮芒果苷元(norathyriol)，对蛋白酪氨酸磷酸酶1B的抑制活性测定、改善胰岛素抵抗作用及在治疗PTP1B相关疾病药物中的应用。通过体外酶抑实验证明，本发明证实芒果苷元是重组人源蛋白酪氨酸磷酸酶1B的竞争型抑制剂，IC50值为9.2μM；芒果苷元可使C57BL/6正常小鼠、ob/ob糖尿病模型小鼠对胰岛素的敏感性明显改善，降低实验动物血糖。说明芒果苷元是PTP1B的新型抑制剂，可作为潜在的先导化合物，在制备治疗胰岛素抵抗相关抗糖尿病和肥胖症等代谢综合征、肿瘤和其他与PTP1B相关疾病的药物中应用。
Description
本申请是申请日为2009年8月21日、申请号为200910184185.5、发明名称为“芒果苷元对PTP1B的抑制活性及其应用”的发明专利申请的分案申请。
技术领域
本发明属于生物制药技术领域，具体涉及芒果苷元对蛋白酪氨酸磷酸酶1B(PTP1B)的抑制活性、改善胰岛素抵抗作用，及在制备治疗II型糖尿病、肥胖等代谢综合征、肿瘤和其他PTP1B相关疾病的药物中的应用。
背景技术
蛋白酪氨酸的磷酸化水平是细胞内信号转导的重要调节因素，它由蛋白酪氨酸激酶(Protein tyrosine kinase，PTK)和蛋白酪氨酸磷酸酶(Protein tyrosine phosphatase，PTP)共同调控，PTP1B(Protein tyrosine phosphatase 1B，PTP1B)属于PTP家族，是胰岛素信号通路中重要的负调控因子并参与瘦素、多种生长因子、催乳素、整合素、血小板凝集素等的信号转导过程，与糖尿病、肥胖的胰岛素抵抗和瘦素抵抗均有密切关系，与胰岛素抵抗、肥胖、血脂代谢紊乱和高血压等4个代谢综合征主要危险因素显著相关，在代谢综合征的发生、发展中起重要作用。PTP1B基因敲除小鼠胰岛素敏感性显著提高，而且能维持很好的糖稳态。另外，PTP1B还能够抑制肿瘤细胞的转移，与肿瘤细胞凋亡、血管生成有关，在乳腺和上皮细胞中催乳激素-泌乳刺激素的信号转导中起负调控作用。PTP1B已成为治疗II型糖尿病、肥胖症、乳腺癌等多种疾病新型、重要的药物靶点，在防治代谢综合征、肿瘤等疾病中起重要作用，对其抑制剂的研究也已经成为目前的研究热点。
芒果苷元(norathyriol，NL)，全称1，3，6，7-四羟基
酮(1，3，6，7-tetrahydroxyxanthone)，其化学结构式如下：
现代药理研究表明，芒果苷元具有多种生理作用，如抗抑郁、抗炎、抗高血压、抗肿瘤、抗氧化及抑制结核杆菌生长等作用，其中抗炎作用的研究较为深入。但目前尚未见其抑制PTP1B、提高胰岛素敏感性方面的研究报道。
发明内容
本发明的目的是致力于研究芒果苷元对蛋白酪氨酸磷酸酶1B的抑制活性，为人们提供一种新的蛋白酪氨酸磷酸酶1B抑制剂，并通过研究芒果苷元对蛋白酪氨酸磷酸酶1B的抑制活性，进一步扩展芒果苷元的药物用途。
为实现上述目的，申请人从以下几个方面进行了研究：
1、建立蛋白酪氨酸磷酸酶抑制活性检测的反应体系，根据PTP1B水解pNPP的磷酸基团而产生颜色反应来检测化学小分子对PTP1B的抑制活性，并用来测定芒果苷元抑制活性包括IC50值和抑制剂类型。
通过上述体外试验，申请人发现芒果苷元可显著抑制PTP1B活性，是一种新型PTP1B抑制剂，其抑制类型为竞争性抑制；
2、通过小鼠的体内试验，申请人发现芒果苷元可显著改善C57BL/6正常小鼠和以胰岛素抵抗为特征的ob/ob糖尿病肥胖模型小鼠的胰岛素敏感性，降低实验动物血糖。
基于上述研究和试验，申请人首次证实了芒果苷元是活性较好的新型PTP1B竞争性抑制剂，在体内可增加胰岛素敏感性，改善实验动物的高血糖症状，可以用于制备提高胰岛素敏感性、降血糖的药物，能成为潜在的治疗II型糖尿病、肥胖等代谢综合征、乳腺癌药的物，并可作为潜在的先导化合物进行抗糖尿病、肥胖等代谢综合征、肿瘤和其他与PTP1B相关疾病的药物进行开发，并可以借助芯片技术等进一步研究代谢相关的信号通路。
附图说明
图1：偏矾酸钠对PTP1B抑制率曲线图。
测定不同浓度的阳性对照物偏矾酸钠(NaVO3)对重组人源蛋白酪氨酸磷酸酶1B抑制率，相对浓度作图，得到NaVO3的IC50为0.32μM。
图2：芒果苷元对PTP1B抑制率曲线图。
测定不同浓度芒果苷元对重组人源蛋白酪氨酸磷酸酶1B抑制率曲线，相对浓度作图，其IC50为9.2μM。
图3：芒果苷元对PTP1B抑制的双倒数图。
在酶存在的条件下，固定抑制剂的浓度，改变底物的浓度，用Lineweaver-Burk法，以1/s为横坐标、1/V为纵坐标作图得到五条回归直线，这五条直线交于Y轴，从而判断芒果苷元对PTP1B的抑制类型为竞争性抑制。
图4：芒果苷元对正常小鼠ip.胰岛素的血糖变化图。
数据用ANOVA法进行统计学处理(n＝11)，其中各组血糖水平与对照组相比，NL(5、40mg/kg)在30、60、90、120min四个时间点有显著性差异*p＜0.05。
图5：芒果苷元对ob/ob小鼠ip.胰岛素的血糖变化图。
数据用ANOVA法进行统计学处理(n＝5)，其中各组血糖水平与对照组相比，NL(40mg/kg)在60、90、120min三个时间点有显著性差异*p＜0.05。
具体实施方式
通过以下实施例进一步详细说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。
材料与来源：
试剂：芒果苷元；重组人源PTP1B(Merck)；对硝基苯磷酸二钠pNPP(Sigma)；偏矾酸钠(Sigma)；MOPS(Sigma)；DTT(Sigma)；胰岛素(江苏万邦生化医药股份有限公司)；C57BL/6小鼠(军事医学科学院实验动物中心)，ob/ob小鼠(Jackson Lab)。
器材：XFLOUR4酶标仪；恒温培养箱；强生稳豪血糖仪
实施例1 芒果苷元对PTP1B的抑制活性测定(IC50值的测定)
芒果苷元用少量DMSO溶解后用MOPS缓冲液稀释，取10μl加入至100μl反应体系中(pH 7.0，25mM mops，1mM EDTA，2mM DTT，0.1M NaCl)，使其终浓度分别为1500、150、15、1.5、0.15μM，加入底物pNPP至16mM，加入重组人PTP1B 5ng后置于37℃反应30min。加10μl 1M NaOH终止反应，置酶标仪上测定405nm波长条件下的吸收值A，以偏矾酸钠(NaVO3)作为阳性对照，以不加PTP1B为空白对照，计算抑制率。用抑制率对浓度做图，得到芒果苷元IC50为9.2μM，偏矾酸钠IC50为0.32μM。
实施例2 芒果苷元对PTP1B的抑制动力学测定
分别配制不同浓度的pNPP(32、16、8、4、2mM)和不同浓度的NL溶液(1.25、2.5、5、10、20μM)。每个NL浓度对应5组pNPP浓度做抑制活性测定，根据OD405的变化求出V，对应的底物浓度为S，根据L-B方程分别作图。结果表明，各条直线交于Y轴，故可判断NL为PTP1B的竞争型抑制剂。
实施例3 芒果苷元在改善正常小鼠胰岛素敏感性方面的作用
C57BL/6小鼠随机分为5组，每组11只，分别为对照组、NL不同剂量给药组(100、60、40、15mg/kg)。给药组分别灌胃给予不同浓度的NL(用0.5％CMC-Na水溶液混悬)，对照组灌胃给予0.5％CMC-Na水溶液。连续给药7天，末次给药后禁食12h，按1U/kg腹腔注射胰岛素，分别于0、15、30、60、90、120min取血测量血糖值。
胰岛素耐量实验(Insulin Tolerance Test，ITT)实验显示，NL(5、40mg/kg)可显著改善C57BL/6小鼠胰岛素敏感性，降低其血糖，在后四个时间点有显著性差异(p＜0.05)。
实施例4 芒果苷元在改善ob/ob小鼠胰岛素敏感性方面的作用
ob/ob小鼠随机分为2组，每组5只，分别为对照组和给药组，给药组灌胃给予40mg/kg NL溶液(用0.5％CMC-Na水溶液混悬)，对照组灌胃给予0.5％CMC-Na水溶液。连续灌胃7天，末次给药后禁食12h，按1U/kg腹腔注射胰岛素，分别在0、15、30、60、90、120min取血测量血糖值。
ITT实验显示，40mg/kg剂量NL可显著改善ob/ob小鼠胰岛素敏感性，降低其高血糖症状，在后三个时间点有显著性差异(p＜0.05)。
Claims (6)
1.一种芒果苷元的用途，其特征在于，用于制备蛋白酪氨酸磷酸酶1B的抑制剂。
2.如权利要求1所述的用途，其特征在于，所述的抑制剂为竞争型抑制剂。
3.如权利要求1或2所述的用途，其特征在于，所述芒果苷元还用于提高胰岛素敏感性，或用作提高胰岛素敏感性的药物。
4.如权利要求1或2所述的用途，其特征在于，所述芒果苷元还用于治疗肥胖症，或用作治疗肥胖症的药物。
5.如权利要求1或2所述的用途，其特征在于，所述芒果苷元还用于治疗PTP1B相关疾病。
6.一种芒果苷元的用途，其特征在于，用于制备通过抑制PTP1B从而治疗肥胖症的药物。
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