CN111138552A - 一种降脂多肽及其制药应用 - Google Patents
一种降脂多肽及其制药应用 Download PDFInfo
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- CN111138552A CN111138552A CN202010040150.0A CN202010040150A CN111138552A CN 111138552 A CN111138552 A CN 111138552A CN 202010040150 A CN202010040150 A CN 202010040150A CN 111138552 A CN111138552 A CN 111138552A
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Abstract
本发明设计了一种新的降脂多肽P48，其能够增加半衰期，发挥其GLP‑1受体激动剂的作用，同时能够发挥GLP‑1类似物的作用调节个体脂肪含量。P48肽能够抑制高脂饮食诱导的非酒精性脂肪肝模型小鼠的进食，显著降低肥胖小鼠体重，降低肥胖小鼠血脂水平，保持肝脏正常形态，抑制肝细胞损伤，降低肝脏内脂质的累积及细胞的空泡变形，提高血液脂联素瘦素的水平，发挥其降糖调脂作用；同时显著改善胰岛素耐量和糖耐量。具有潜在制备治疗和预防肥胖或其并发症非酒精性脂肪肝药物的制药应用。
Description
技术领域
本发明属于药学及医学相关技术，特别是涉及一种新型降脂多肽，及其在制备治疗或预防肥胖及其并发症等药物中的应用。
背景技术
截至2014年，全球共有19亿成人超重，其中超过6亿人为肥胖。当生活方式干预无效，即不能使体重减轻5％，BMI指数仍大于28时，推荐其进行药物治疗；超重且伴有一种并发症(心血管疾病、高血压、2型糖尿病等)的患者，经生活干预无效，也推荐其进行药物治疗。全球有超过10亿患者需要药物治疗。改变生活方式是肥胖治疗的主要方法，仅仅依赖于饮食控制的来维持长期减肥较为困难，虽然已经研究出了许多治疗肥胖的手段，但多存在毒副作用及不良反应。因此，研究和开发针对肥胖的药物具有重要的科学意义和社会价值。
非酒精性脂肪肝(NAFLD)表现为一系列的肝脏疾病，从简单脂肪变性到其更严重的形式，称为非酒精性脂肪性肝炎(NASH)，肝细胞损伤，肝脏炎症，常伴有纤维化。患者通常肥胖或患有2型糖尿病(T2DM)，并且发生肝硬化和肝细胞癌的风险增加。据研究表明，NAFLD将在2020年之前成为肝移植的主要原因，肥胖症流行的增加，约70％以上的肥胖个体(特别是T2DM)患有NAFLD，他们其中50％可能患有NASH。NASH的发展也与心血管疾病(CVD)的死亡风险相关，该疾病已成为欧美等国家和我国富裕地区慢性肝病的主要病因，改变生活方式是肥胖治疗的主要方法，仅仅依赖于饮食控制的来维持长期减肥是较为困难的，虽然已经研究出了许多治疗NASH的手段，但是没有一个经FDA批准。因此，研究和开发针对非酒精性脂肪肝的药物具有重要的科学意义和社会价值。
胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)是由胰高血糖素原基因编码，后经加工修饰得到的30个氨基酸的肠降血糖素(incretin)。主要由小肠黏膜的L细胞合成并分泌，在胰岛的α细胞也有表达。GLP-1具有两种生物活性形式，GLP-1(7-37)和GLP-1(7-36)酰胺，血液循环中主要以GLP-1(7-36)酰胺的活性形式存在，两者具有共同的生物学活性。
天然人GLP-1的稳定性较差，易被二肽基肽酶Ⅳ(DPPⅣ)降解，并快速被肾脏清除,其半衰期t1/2≤2min。GLP-1经DPPⅣ切割掉N末端His-Ala，生成GLP-1(9-36)氨基多肽，最初研究认为，GLP-1(9-36)氨基多肽不具有生物学活性，而且对GLP-1受体(GLP-1R)还具有一定的拮抗作用，近些年发现GLP-1(9-36)氨基多肽具有类胰岛素的作用。
GLP-1的生理作用主要包括三个部分，一是通过与GLP-1R结合，发挥生理学效应，包括：①葡萄糖依赖性促胰岛素分泌；②抑制胰高血糖素分泌；③延迟胃排空，降低食欲，减少饮食，控制体重；④抑制β细胞凋亡，促进β细胞增值和分化。二是，GLP-1经过DPPⅣ降解，生成GLP-1(9-36)氨基多肽，能够抑制肝脏糖异生酶和脂肪酸合酶的表达，抑制糖异生和肝脏脂肪合成，发挥类胰岛素作用。三是GLP-1(9-36)氨基多肽经过肽链内切酶(NEP 24.11)切割成GLP-1(32-36)氨基5肽，在肥胖型小鼠上增加能量消耗，抑制体重增长。
发明内容
发明目的：针对上述现有技术，本申请设计了一条新的降脂多肽，并提供了所述降脂多肽在制备治疗和预防肥胖及其并发症(非酒精性脂肪肝)药物中的应用。
技术方案：本发明所述的一种降脂多肽，代号P48，氨基酸序列如SEQ ID NO：1所示。
SEQ ID NO：1
HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRGSSGAPPPSEYVTLKKMREIIGWPGGSGD
本发明还公开了所述降脂多肽在制备治疗或预防肥胖药物中的应用。
本发明还进一步公开了所述降脂多肽在制备治疗或预防肥胖并发症非酒精性脂肪肝药物中的应用。
本发明所述的一种药物组合物，包括上述的降脂多肽和/或其衍生物和类似物，以及药物载体。
本发明还进一步公开了所述药物组合物在制备治疗或预防肥胖症药物或者肥胖并发症非酒精性脂肪肝药物中的应用。
本发明利用计算机辅助分析的方法，将GLP-1和艾塞那肽(Exendin-4)以及谷氨酸脱羧酶(GAD，Glutamate decarboxylase)中部分氨基酸顺序打乱后得到的一条59肽，即P48肽，其获得比上述三者更强的药效和新的作用机制，能有效改善NAFLD模型小鼠的病理状况。
有益效果：本发明通过氨基酸替换和末尾添加小肽片段，构建了一种新型降脂P48肽。并且通过实验结果证明P48肽能够显著降低肥胖小鼠体重，并能够轻微抑制进食。生化指标检测及病理切片观察发现，P48能够降低肥胖个体血脂水平，抑制肝细胞损伤，降低肝脏内脂质的累积及细胞的空泡变形(优于正常饮食对照组，HE染色，油红O染色)，提高血清中肥胖抵抗因子(瘦素，脂联素)的水平。对比市面上已有类似物(利拉鲁肽)和临床常用肝脏保护药物(熊去氧胆酸)具有有效性更好，作用更明显，具有潜在的制药应用前景。胰岛功能的研究发现，P48能够显著改善NAFLD模型小鼠葡萄糖耐量，同时显著提高小鼠胰岛素敏感性。
附图说明
图1 P48对NAFLD模型小鼠累计进食的影响；
图2 P48对NAFLD模型小鼠体重的影响；
图3 P48对NAFLD模型小鼠血脂的影响(Cholesterol,HDL-C,LDL-C)；
图4 P48对NAFLD模型小鼠肝细胞损伤的影响；
图5 P48对NAFLD模型小鼠肝脏脂肪变性(HE染色)的影响；
图6 P48对NAFLD模型小鼠肝脏脂肪累积(油红O染色)的影响；
图7 P48对NAFLD模型小鼠的瘦素(Leptin)水平的影响；
图8 P48对NAFLD模型小鼠的脂联素(Adiponectin)水平的影响；
图9 P48对NAFLD模型小鼠胰岛素耐量的影响(IPITT)；
图10 P48的糖依赖性的促胰岛素分泌作用(IPGTT)。
具体实施方式
下面结合实施例对发明做进一步详细说明。
本发明降脂肽P48根据GLP-1的野生型进行改造，第2位的氨基酸由Ala替换成Gly，在GLP-1的末尾添加Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Glu-Tyr-Val-Thr-Leu-Lys-Lys-Met-Arg-Glu-Ile-Ile-Gly-Trp-Pro-Gly-Gly-Ser-Gly-Asp，延长其半衰期。序列如下：
GLP-1：HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG
Exendin-4:HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGP
P48：
实施例1：P48的药效学评价
1、NAFLD模型小鼠造模，及分组
50只8周龄的雄性c57小鼠(购自南京大学-南京生物医药研究院，许可证号：SCXK(苏)2016-0011)，适应性饲养1周，后持续28周的高脂肪饲料(HFD，D12492,购自ResearchDiets)饲喂，使小鼠体重增加，在第14周小鼠体重均大于50g时为造模成功。将成模小鼠随机分成4组，每组10只，分别为空白对照组(Chow，D12450J，购自Research Diets，对照饲料喂养，正常体重，空白对照组)，溶剂对照组(Vehicle，阴性对照组)、利拉鲁肽组(Liraglutide，阳性对照组，购自南京莱昂生物科技有限公司)、熊去氧胆酸组(UDCA，Ursodeoxycholic Acid，阳性对照组，购自上海鼓臣生物技术有限公司)，P48组(实验组)。给药剂量为50nmol/kg，每天2次，溶剂为生理盐水，皮下注射0.1ml，固定时间点给药，AM 9：00-10:00，PM 8:00-9:00。阴性对照组，皮下注射0.1ml生理盐水，空白对照组不做处理。
2、对NAFLD模型小鼠累计进食的影响
从给药开始，每组分别记录初始添食量，隔1天或2天检测剩食量，并继续添加新的鼠粮，并记录，依次类推，到12周给药结束，记录小鼠的总进食量，并绘制累计进食曲线，结果如图1，根据图示可见，P48组累计进食明显少于溶剂组、UDCA组和Liraglutide组，P48组和Liraglutide组都具有抑制进食的效果。
3、对NAFLD模型小鼠体重的影响
小鼠空腹8小时，AM 8:00开始禁食，PM 4:00，称量小鼠体重，作为给药0周体重。之后分别在给药每周，检测空腹体重，禁食时间和检测时间同0周方法，结果如图2，P48组能够显著降低NAFLD模型小鼠的空腹体重，明显优于溶剂组，UDCA组和Liraglutide组，到第2周，与溶剂组比较，p***≤0.001，具有显著性差异。到第12周，P48组与空白对照组小鼠体重比较，无显著性差异，与Liraglutide组比较，p###≤0.001。结果说明，P48处理后能够明显降低NAFLD模型小鼠的体重，且减重效果优于Liraglutide组。
4、对NAFLD模型小鼠血脂水平的影响
给药12周后，眼眶取血，静置收集血清，使用试剂盒分别检测总胆固醇(CHO)，低密度脂蛋白(LDL-C)和高密度脂蛋白(HDL-C)水平，结果如图3。结果显示，血清胆固醇水平，P48组与模型组比较，p***≤0.001，具有极显著性差异，Liraglutide组与模型组比较，p***≤0.001，P48组与空白对照组比较，无显著性差异；血清低密度脂蛋白水平，P48组与模型组比较具有显著性差异，p***≤0.001，Liraglutide组与模型组比较，p*≤0.05，P48组与空白对照组比较，无显著性差异；血清高密度脂蛋白水平，P48组与模型组比较具有显著性差异，p≤0.001，Liraglutide组与模型组比较，p***≤0.001，P48组与空白对照组比较，无显著性差异。结果说明，P48处理后能够明显降低NAFLD模型小鼠的总胆固醇，低密度脂蛋白和高密度脂蛋白水平，低密度脂蛋白水平低于Liraglutide组。
5、对NAFLD模型小鼠肝脏细胞的影响
给药12周后，处死小鼠，眼眶取血，静置收集血清，使用试剂盒分别检测谷丙转氨酶(ALT)和谷草转氨酶(AST)水平，结果如图4。结果显示，血清谷丙转氨酶(ALT)水平，P48组与模型组比较，p***≤0.001，具有极显著性差异，Liraglutide组与模型组比较，p***≤0.001，P48组与空白对照组比较，无显著性差异；血清谷草转氨酶(AST)水平，P48组与模型组比较，p***≤0.001，具有极显著性差异，Liraglutide组与模型组比较，p***≤0.001，P48组与空白对照组比较，无显著性差异。当肝细胞发生炎症、中毒、坏死等时会造成肝细胞的受损，转氨酶便会释放到血液里，使血清转氨酶升高。结果说明，P48和Liraglutide处理后能够明显降低NAFLD模型小鼠的肝细胞损伤。
给药12周后，处死小鼠，取肝脏，用福尔马林固定，经HE染色和油红O染色后，观察肝脏细胞，结果如图5，图6。模型组和UDCA组肝细胞损伤严重，有大量气球样空泡及脂肪堆积，Liraglutide组和P48组肝脏细胞与模型组相比得到明显改善，可以观察到少量气球样空泡或无空泡，少量脂肪堆积或无脂肪堆积，p***≤0.001；P48组空泡数量和脂肪含量小于Liraglutide组，p***≤0.001。肝脏脂肪变性的主要特征是肝细胞胞质内出现空泡及过度脂肪堆积。结果说明Liraglutide组和P48组均能改善肝脏脂肪变性，减少肝脏细胞内的脂肪堆积，且P48组效果优于Liraglutide组。
6、对NAFLD模型小鼠肥胖抵抗因子水平的影响
给药12周后，眼眶取血，静置收集血清，使用试剂盒检测瘦素(Leptin)和脂联素(Adiponectin)水平，结果如图7，图8。结果显示，瘦素(Leptin)水平，P48组与模型组存在显著差异，p***≤0.001，Liraglutide组与模型组存在显著差异，p***≤0.001，P48组与模型组存在显著差异，p*≤0.05；脂联素(Adiponectin)水平，P48组与模型组存在显著差异，p***≤0.001，Liraglutide组与模型组比较，无显著性差异；说明P48处理后能够明显增加NAFLD模型小鼠的肥胖抵抗因子水平，优于Liraglutide组。
7、糖依赖性的促胰岛素分泌作用(IPTGG)
第9周，小鼠空腹8小时，AM 8:00开始禁食，PM 4:00，尾静脉检测空腹血糖，检测用血糖检测仪(欧姆龙血糖仪HEA-231型)，测空腹血糖，分别注射肽或者溶剂，30分钟注射葡萄糖(1.5g/kg)，之后分别在注射葡萄糖之后15、30、60、120分钟检测血糖，并分别计算曲线下面积。结果P48具有葡萄糖依赖性的促胰岛素分泌功能，与溶剂组有显著性差异。结果如图9所示，效果优于Liraglutide组。
8、对NAFLD模型小鼠胰岛素耐量的影响
第9周，小鼠空腹8小时，AM 8:00开始禁食，PM 4:00，尾静脉检测空腹血糖，检测用血糖检测仪(欧姆龙血糖仪HEA-231型)，检测空腹血糖，作为胰岛素耐量的0点血糖，按1IU/kg的剂量皮下注射胰岛素，之后分别在注射胰岛素之后15、30、60、90、120分钟检测血糖，并分别计算曲线下面积，结果如图10所示。结果P48显著改善胰岛素耐量，与溶剂组和Liraglutide组均具有显著性差异，p***≤0.001。结果说明P48处理后能够明显增加NAFLD模型小鼠的胰岛素敏感性，且优于Liraglutide组。
序列表
<110> 中国药科大学
<120> 一种降脂多肽及其制药应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 59
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser Glu Tyr Val Thr Leu Lys Lys Met Arg
35 40 45
Glu Ile Ile Gly Trp Pro Gly Gly Ser Gly Asp
50 55
Claims (6)
1.一种降脂多肽，其特征在于，其氨基酸序列如SEQ ID NO：1所示。
2.权利要求1所述降脂多肽在制备治疗或预防肥胖药物中的应用。
3.权利要求1所述降脂多肽在制备治疗或预防非酒精性脂肪肝药物中的应用。
4.一种药物组合物，其特征在于，包括权利要求1所述的降脂多肽和/或其衍生物和类似物，以及药物载体。
5.权利要求4所述药物组合物在制备治疗或预防肥胖药物中的应用。
6.权利要求4所述药物组合物在制备治疗或预防非酒精性脂肪肝药物中的应用。
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