CN104262468B - 一种葡萄糖转运蛋白抑制多肽及其制备方法、应用 - Google Patents
一种葡萄糖转运蛋白抑制多肽及其制备方法、应用 Download PDFInfo
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Abstract
一种葡萄糖转运蛋白抑制多肽及其制备方法、应用，本发明涉及药物领域，具体涉及多肽1化合物，能治疗糖尿病。所述的多肽1序列为MEPSSKKLTGIFAGGSVGGMIGS。所述多肽1的制备方法，采用Fmoc保护的固相合成技术制备，可共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。所述多肽1在治疗糖尿病及糖尿病并发症中的应用。所述的糖尿病并发症是糖尿病肾病、糖尿病高血压、糖尿病眼疾、糖尿病神经性病变。多肽1可通过多种给药方式治疗糖尿病及糖尿病并发症，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂等。本发明中的葡萄糖转运体蛋白抑制多肽1，可以靶向抑制葡萄糖转运体蛋白，达到预防或治疗糖尿病的效果。
Description
技术领域：
本发明涉及药物领域，具体涉及用于治疗糖尿病的多肽化合物。
背景技术
糖尿病是一组以高血糖为特征的代谢性疾病，是由于胰岛素不足或胰岛素的细胞代谢作用缺陷所引起的葡萄糖、蛋白质及脂质代谢紊乱的一种综合症。近年来，糖尿病患者的人数逐渐增多，分为I型糖尿病和II型糖尿病。其中II型糖尿病患者的人数占糖尿病总人数的85-90％，严重威胁着病人的健康和生命。如果糖尿病得不到良好的控制，可能引起很多并发症，例如：糖尿病肾病、视网膜病变、高血压等。
目前，大多数患者通过口服降糖药物来帮助控制体内血糖，或调节胰岛素分泌等，很多患者最终仍然要使用胰岛素治疗。
葡萄糖的代谢取决于细胞对葡萄糖的摄取，然而，葡萄糖无法自由通过细胞膜脂质双层结构进入细胞，细胞对葡萄糖的摄入需要借助细胞膜上的葡萄糖转运蛋白(glucosetransporters)简称葡萄糖转运体(GLUT)转运功能才能得以实现。
抑制葡萄糖转运体转运功能就可以抑制体内葡萄糖的摄入，缓解体内高血糖的症状，因此，葡萄糖转运体转运抑制认为是治疗糖尿病的靶点。尽管如此，并没有成熟开发的葡萄糖转运体转运抑制剂问世，用于治疗糖尿病。
发明内容：
本发明目的是针对现有降血糖的药物的特点，设计一种多肽1化合物，能有效治疗糖尿病。
技术方案
一种葡萄糖转运蛋白抑制多肽1，其序列为MEPSSKKLTGIFAGGSVGGMIGS。所述多肽1的制备方法，其特征在于：采用Fmoc保护的固相合成技术制备，可共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。所述多肽1在治疗糖尿病及糖尿病并发症中的应用。所述的糖尿病并发症是糖尿病肾病、糖尿病高血压、糖尿病眼疾、糖尿病神经性病变。多肽1可通过多种给药方式治疗糖尿病及糖尿病并发症，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂等。
有益结果：
本发明中的葡萄糖转运体蛋白抑制多肽1，可以靶向抑制葡萄糖转运体蛋白，达到预防或治疗糖尿病的效果。更优选是治疗糖尿病和/或糖尿病并发症药物中的用途。所述的糖尿病包括I型糖尿病和II型糖尿病；所述的糖尿病并发症包括但不限于：糖尿病肾病、糖尿病高血压、糖尿病眼疾、糖尿病神经性病变等。
具体实施方式
实施例1
多肽的化学合成方法
多肽1用Fmoc保护的固相合成技术制备。合成反应按照多肽1序列从C端向N端进行，Rink介质(可在Advanced Chem Tech公司购得)上有自由氨基。每一步连接过程中，氨基酸残基都要活化，活化混合物中有4倍于介质上自由氨基的HBTU，HOBt，DIEA和Fmoc-氨基酸。每次氨基酸的连接反应之后，都用一个吡啶/醋酸/N-甲基咪唑(4:1:0.5)的混合物来封闭未连接的自由氨基，封闭反应10分钟。每次氨基酸的连接反应之后，下一个氨基酸连接之前，都要把介质上的Fmoc-基团去掉，去Fmoc-基团使用含20％哌啶的二甲基甲酰胺，需15分钟。最后，当所有氨基酸残基顺序连接之后，多肽1用98％三氟乙酸从介质上切割下来，切割在室温下进行2小时。
应用上述化学条件可合成并获得多肽1，序列为MEPSSKKLTGIFAGGSVGGMIGS，该序列为全新序列。
实施例2
葡萄糖转运体蛋白抑制多肽1的体外细胞活性测定
采用MTT比色法。将对数生长的胰岛瘤细胞(INS-1细胞)，以1.0×105加入96孔培养板中，培养24h，实验孔、阳性药物对照孔分别加入不同浓度的实验药物葡萄糖转运体蛋白抑制多肽1；空白组加入相同体积的溶剂。每孔设五个复孔，培养48h，每孔加入MTT，作用4h后，加入DMSO，孵育30min，在酶标仪570nm处测定吸光度A值，按公式细胞生长增殖率＝(实验组吸光值/对照组吸光值-1)×100％。计算出实验药物的EC50为7.13nmol/L。
实施例3
葡萄糖转运体蛋白抑制多肽1的体内降糖实验
昆明小鼠，高脂高糖喂养至体重18～22g，雌雄各半，实验前禁食不禁水24h，腹腔一次性注射链脲佐菌素(STZ)50mg/kg(1％的柠檬酸盐缓冲液溶解配制)。1周后小鼠尾静脉采血测血糖(BS)，BS高于16mmol/L为造模成功。造模后将小鼠分为3组，每组10只，糖尿病模型组(DM组)：给予等量的PBS缓冲液皮下注射；对照组(拜糖平)：20μg/kg皮下注射给药(溶于0.1mol/L PBS缓冲液)，一天两次，连续15d；样品组(葡萄糖转运体蛋白抑制多肽1)：同对照组；另取10只正常小鼠做为空白组。用药后第3d、9d、15d于尾静脉取血快速测量血糖。15d之后，在停药1周后，禁食不禁水16小时进行葡萄糖耐量试验。用25％葡萄糖溶液(2g/kg)灌胃，灌胃后0、30、60、120分钟尾静脉取血检测血糖。
结果：葡萄糖转运体蛋白多肽1具有降低糖尿病模型小鼠血糖的作用(P<0.05，表1)；同时，可以缓解糖尿病模型小鼠的糖耐量(表2)。其多肽1的作用与对照组拜糖平作用相当。
表1 葡萄糖转运体蛋白抑制多肽1对小鼠降血糖作用
*p<0.05，**p<0.01与模型组相比
表2 葡萄糖转运体蛋白抑制多肽1对小鼠糖耐量实验结果
*p<0.05，**p<0.01与模型组相比
结论：葡萄糖转运体蛋白抑制多肽1对糖尿病小鼠具有治疗作用。
SEQUENCE LISTING
<110> 苏州普罗达生物科技有限公司
<120> 一种葡萄糖转运蛋白抑制多肽及其制备方法、应用
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 23
<212> PRT
<213> 人工序列
<400> 1
Met Glu Pro Ser Ser Lys Lys Leu Thr Gly Ile Phe Ala Gly Gly Ser
1 5 10 15
Val Gly Gly Met Ile Gly Ser
20
Claims (2)
1.一种葡萄糖转运蛋白抑制多肽，其特征在于：其氨基酸序列为MEPSSKKLTGIFAGGSVGGMIGS。
2.一种如权利要求1所述的多肽在制备治疗糖尿病及糖尿病并发症药物中的应用；所述的糖尿病并发症是糖尿病肾病、糖尿病高血压、糖尿病眼疾、糖尿病神经性病变。
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