CN105504010A - 一种具有dpp-iv抑制活性的多肽及其应用 - Google Patents
一种具有dpp-iv抑制活性的多肽及其应用 Download PDFInfo
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Abstract
本发明涉及一种源于鹿蛋白的DPP-IV抑制肽GPGSPGGPL，其氨基酸序列为Gly-Pro-Gly-Ser-Pro-Gly-Gly-Pro-Leu。多肽GPGSPGGPL具有DPP-IV抑制活性及降血糖活性，作为糖尿病、心脏病、心血管病、肥胖症、肾病、免疫紊乱等疾病的保健品和药物先导化合物具有良好的应用前景。
Description
技术领域
本发明涉及多肽GPGSPGGPL在制备抑制二肽基肽酶—IV(DPP-IV)及降血糖中的应用。
背景技术
二肽基肽酶—IV(dipeptidylpeptidase-IV，DPP-IV)(EC3.4.14.5)是一种丝氨酸蛋白酶，广泛分布于人体内。DPP-IV通过对多肽的剪切使其失活，从而达到调节生理功能的作用。DPP-IV优先水解N-末端第二位上具有脯氨酸(Pro)或丙氨酸(Ala)的蛋白质。其作用底物包括：胰高血糖素样肽-1(GLP217-36)、抑胃肽(GIP1-42)、神经肽(NPY)、YY肽(PYY)以及胰多肽家族(PP-family)等。这些物质的共同特点就是N-末端第二位的氨基酸残基或者是脯氨酸或者是丙氨酸残基。DPP-IV通过作用于以上多肽底物而在糖尿病、葡萄糖耐量、肥胖、食欲调节、高血脂症、骨质疏松、神经肽新陈代谢和T-细胞激活等相关疾病中起着重要的作用。因此，体内给予DPP-IV抑制剂可预防相关底物肽的N-末端降解，从而保障人体机能正常运行。
DPP-IV将完整的GLP-1和GIP反应切断N-末端2个氨基酸残基后，使其失活从而影响GLP-1和GIP相关的血糖调节等生理反应。体内给予DPP-IV抑制剂可预防GLP-1和GIP的N-末端降解，使胰岛素分泌物增加从而改善葡萄糖耐量。鉴于DPP-IV抑制剂与血糖代谢的密切关系，DPP-IV抑制剂已成为新型2型糖尿病药物的研究热点。
发明内容
本发明的目的是提供多肽GPGSPGGPL在抑制DPP-IV活性和降血糖中的应用；多肽GPGSPGGPL具有DPP-IV抑制活性及降血糖活性，作为糖尿病、心脏病、心血管病、肥胖症、肾病、免疫紊乱等疾病的保健品和药物先导化合物具有良好的应用前景。
为实现上述目的，本发明以所述多肽GPGSPGGPL为抑制DPP-IV活性和降血糖的有效成份。
其具有序列表SEQIDNO：1中氨基酸序列；多肽GPGSPGGPL为DPP-IV抑制剂及降血糖药物的活性成份，其中可添加药物学上可接受的载体或辅料。
具有抑制DPP-IV活性和降血糖活性的多肽化合物GPGSPGGPL的氨基酸序列为Gly-Pro-Gly-Ser-Pro-Gly-Gly-Pro-Leu。单链线性结构，分子量为738.8Da，白色粉末状，易溶于水，对DPP-IV活性具有很强的抑制作用，IC50为1.64mM。
多肽GPGSPGGPL具备DPP-IV抑制剂所要求的特征：DPP-IV优先水解N-末端第二位上具有脯氨酸(Pro)或丙氨酸(Ala)的蛋白质或肽，GPGSPGGPL的N-末端第二位上是脯氨酸(Pro)。
本发明与现有技术相比，具有如下有益效果：
本发明首次从鹿蛋白中获得并确定了活性化合物的结构，化合物具有较好的抑制DPP-IV的活性，因此作为糖尿病、心脏病、心血管病、肥胖症、肾病、免疫紊乱等疾病的保健品和药物先导化合物具有良好的应用前景。
具体实施方式
实施例1多肽GPGSPGGPL的制备
100g新鲜的马鹿鹿皮，用质量浓度10％NaOH于50℃煮30分钟进行脱脂处理后，纯水清洗干净，剪为2～3平方厘米的碎片。鹿皮碎片按照1:100(原料：缓冲液质量比)加入0.01M醋酸缓冲液，再按1:100(酶：原料)质量比加入胃蛋白酶，于40℃搅拌反应2小时。将上述反应液的pH用1MNaOH调至7，加入复合酶(糜胰蛋白酶，中性蛋白酶，质量混合比例1:1)进行酶解，加酶量为反应物质量的0.1％，于40℃搅拌反应2小时，反应结束后90℃灭活20min。将上述反应液5000rpm离心5min，收集上清，上述酶解产物经制备色谱分离，色谱柱为C18(20X250mm，10μm),所用的流动相A为质量浓度0.1％甲酸/水溶液，流动相B为质量浓度0.1％的甲酸/乙腈溶液，流速为2mL/min，洗脱过程如下：5％B—35％B(V/V)—80％B(V/V)。将在280nm下所检测到的色谱峰分别收集得到不同组分冷冻干燥，为乳白色粉末状样品。
所得样品分别经反相液相色谱-串联质谱系统(RPLC-MS/MS)分析：将冷冻干燥后的酶解样品用体积浓度0.1％甲酸溶液配制为0.4μg/μL，进样20μL进行LTQ线性离子阱质谱(配置纳升级电喷雾源)分析。利用Xcalibur软件(Thermo)进行系统控制和数据收集。实验得到的质谱数据结果分别在honeybee,BrassicacampestrisL.蛋白质数据库(http://www.uniprot.org/)中进行检索，技术重复3次，数据库检索软件为SEQUEST。获得序列为Gly-Pro-Gly-Ser-Pro-Gly-Gly-Pro-Leu。
实施例2多肽GPGSPGGPL的DPP-IV抑制活性检测
(1)原理
采用以甘氨酰脯氨酸对硝基苯胺(Gly-Pro-PNA)为底物的发色底物法筛选DPP-IV抑制剂，该方法的检测原理为在碱性条件下DPP-IV催化底物Gly-Pro-p-nitroanilide水解,生成黄色的对硝基苯胺,后者在波长405nm处有特征性吸收峰，通过酶标仪在405nm处测得的吸光度大小反映酶活性高低。
(2)方法
样品：将样品溶解于100mM的Tris-HCl缓冲液(pH＝8.0)，配成40mg/mL储备液，再将储备液稀释成不同的浓度，作为样品溶液。
底物：Gly-pro-p-nitroanilide溶液，用100mM的Tris-HCl缓冲液(pH＝8.0)将Gly-pro-p-nitroanilide配置成1.59mM的Gly-pro-p-nitroanilide溶液。
酶：DPP-IV溶液，用100mM的Tris-HCl缓冲液(pH＝8.0)配置成0.01U/mL的DPP-IV溶液。
终止溶液：1M的醋酸—醋酸钠缓冲液(pH＝4.0)。
实验在96孔板中进行，利用酶标仪在405nm检测吸光度。首先将酶、缓冲液及药物在37℃温度下分别水浴30min,然后将样品(或缓冲液)、底物依次加入96孔板内37℃孵育10分钟，再加入DPP-IV酶溶液，混匀后于37℃温育60分钟，加入100μL1M的醋酸-醋酸钠缓冲液(pH4.0)使反应终止。用酶标仪测定405nm吸光度(OD)。反应总体积为100μl。实验分为4组,每组设3个复孔。各组分别为：
样品组(S组)：样品+酶+底物。
样品空白组(SB组)：样品+底物。
阴性对照组(C组)：酶+底物。
空白组(B组)：底物。
具体各组加样品见表1。
表1DPP-VI抑制活性实验分组及加样量
注：(1)表中数字的单位均为μl。
(2)反应总体积为100μl，各组按照表中所列加入反应物后用缓冲液将最终体积补至100μl。
(3)抑制率的计算
(4)检测结果
分别用12.5μg/ml,25μg/ml，50μg/ml，100μg/ml，250μg/ml，500μg/ml的多肽浓度，按上述方法进行DPP-IV抑制活性检测。结果如下表：
经IC50计算器计算该序列的IC50为1.21mg/mL，即1.64mM。
Claims (4)
1.具有DPP-IV抑制活性的多肽，其特征在于：所述多肽为GPGSPGGPL，具有序列表SEQIDNO：1中氨基酸序列；该多肽的氨基酸序列具体为，Gly-Pro-Gly-Ser-Pro-Gly-Gly-Pro-Leu。
2.一种权利要求1所述多肽在制备DPP-IV抑制剂或降血糖药物中的应用。
3.按照权利要求2所述的应用，其特征在于：所述DPP-IV抑制剂及降血糖药物是以多肽GPGSPGGPL为活性成份，其中可添加药物学上可接受的载体或辅料。
4.按照权利要求2所述的应用，其特征在于：所述多肽在制备预防和/或治疗糖尿病、心脏病、心血管病、肥胖症、肾病、免疫紊乱中的一种或二种以上疾病药物和/或保健品中的应用。
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| CN110776557A (zh) * | 2018-07-27 | 2020-02-11 | 中国科学院大连化学物理研究所 | 多肽及其应用和dpp-ⅳ抑制剂或降血糖药物或保健品 |
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