CN112023028B - 长效glp-1类似物多肽的减肥用途 - Google Patents
长效glp-1类似物多肽的减肥用途 Download PDFInfo
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- CN112023028B CN112023028B CN202010825858.7A CN202010825858A CN112023028B CN 112023028 B CN112023028 B CN 112023028B CN 202010825858 A CN202010825858 A CN 202010825858A CN 112023028 B CN112023028 B CN 112023028B
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Abstract
本发明涉及一种长效GLP‑1类似物多肽的减肥用途，其氨基酸序列为：HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRGPGHGEGTFTSDVSSYLEGQAAKEFIAWLVKGRGP。该多肽可用于制备减肥、治疗或预防肥胖的药物或药物组合物。本发明多肽能够有效地发挥抑制进食和基础能量消耗功能；针对高脂诱导的肥胖模型小鼠，能抑制其进食，减轻体重，降低脂肪含量，改善血清指标，增加耗氧量，改善脂肪肝；其减轻体重的作用明显优于Exendin‑4和GLP‑1。
Description
技术领域
本发明涉及一种长效GLP-1类似物多肽的减肥用途，属于生化药学技术领域。
背景技术
胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)是小肠L细胞分泌的维持血糖的重要激素。GLP-1在体内以三种形式存在：第一种形式为全长GLP-1，包含37个氨基酸残基GLP-1(1-37)；第二种形式为氨基端截断的GLP-1(7-37)；第三种形式为一个酰胺化的氨基端截断的GLP-1(7-36)酰胺。其中，GLP-1(1-37)是无活性的形式，GLP-1(7-37)与GLP-1(7-36)酰胺是两种主要的活性形式。
GLP-1在体内发挥多种生物学功能，其作用位置包括胰腺、胃、脑、心脏、肝脏、脂肪和肌肉等。其中，在胰腺、胃肠、神经系统、心脏等位置主要是通过直接激活GLP-1R发挥相应的生物学功能，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细胞增值和分化等。而在肝脏、脂肪和肌肉中的生理作用一般认为是间接的生理作用。现在有学者提出双受体假说，认为GLP-1(7-37)和GLP-1(7-36)酰胺的DPP-IV的降解产物GLP-1(9-37)和GLP-1(9-36)酰胺起到了关键的作用，通过新的GLP-1R来发挥生理作用。
虽然GLP-1具有多种生理作用，但是其半衰期较短，在体内的半衰期只有1～2min，严重限制了GLP-1成药性的应用。虽然市场上已经有多种GLP-1R激动剂，如艾塞那肽，利拉鲁肽等，虽然是很好的GLP-1R激动剂，但是不具备GLP-1小分子的间接功能。目前亟待研发小分子长效GLP-1类似物以作为药物治疗的主要选择。
发明内容
本发明的目的在于：针对上述现有技术存在的问题，提出一种长效GLP-1类似物多肽的减肥用途，该多肽相比于GLP-1具有更长的作用时长。
本发明解决其技术问题的技术方案如下：
一种长效GLP-1类似物多肽用于制备减肥药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
一种长效GLP-1类似物多肽用于制备治疗或预防肥胖的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
一种长效GLP-1类似物多肽用于制备体脂含量的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
一种长效GLP-1类似物多肽用于制备治疗或预防脂肪肝病的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
一种长效GLP-1类似物多肽用于制备降低脂肪细胞大小和/或减少肝脏组织脂肪空泡的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ IDNo.1所示。
一种长效GLP-1类似物多肽用于制备增高高密度脂蛋白且降低甘油三酯、胆固醇以及低密度脂蛋白的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
一种长效GLP-1类似物多肽用于制备增加基础耗氧量的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
上述用途中，所述多肽为多肽自身或其药用盐。
上述用途中，所述药物组合物包括药物载体。
上述用途中，所述药物组合物包括药物活性物质。
本发明多肽(PEP6)根据GLP-1的野生型进行改造，在GLP-1的末尾添加人工肽(PGHADGTFTSDYSSYLEGQAAKKFIQWLVNGEGPPP)，延长其半衰期(持续作用时间可长达8小时，与GLP-1相比有显著提高)，能够减少肥胖小鼠的体重，减少脂肪含量与内脏脂肪含量；减少肥胖小鼠血清中甘油三酯、胆固醇、低密度脂蛋白含量，升高高密度脂蛋白及游离脂肪酸含量；改善脂肪肝。
附图说明
图1为本发明实施例1中糖依赖性的促胰岛素分泌作用检测结果图。
图2为本发明实施例1中降糖持续时间检测结果图。
图3为本发明实施例2中进食曲线和体重的检测结果图。
图4为本发明实施例2中体脂含量的检测结果图。
图5为本发明实施例2中白色脂肪、肝脏的检测结果图。
图6为本发明实施例2中血清指标的检测结果图。
图7为本发明实施例2中耗氧量的检测结果图。
具体实施方式
下面参照附图并结合实施例对本发明作进一步详细描述。但是本发明不限于所给出的例子。
实施例1
本实施例为检测PEP6肽的糖依赖性促胰岛素分泌作用(IPTGG)以及作用时长。
其中，PEP6肽即本发明多肽，其氨基酸序列为：
HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRGPGHADGTFTSDYSSYLEGQAAKKFIQWLVNGEGPPP，如SEQ ID No.1所示。
本实施例的具体过程如下：
8周龄的雄性C57BL/6小鼠，随机分为6组，每组8只，分别为溶剂对照组(Vehicle组)、GLP-1组(30nmol/kg)、PEP6组(0.1nmol/kg)、PEP6组(1nmol/kg)、PEP6组(30nmol/kg)、PEP6组(100nmol/kg)进行糖耐量实验。注：均为皮下注射。
结果如图1所示，与对照组相比，GLP-1、PEP6均能够显著降低血糖值，且曲线下面积与对照组相比明显降低，这表明PEP6能够与GLP-1一样具有糖依赖性的促胰岛素的分泌作用，同时，PEP6(0.1、1、30、100nmol/kg)能够剂量依赖性的降低血糖，且最小起效浓度为0.1nmol/kg。
为进一步评估PEP6在体内的代谢水平，采用8周龄的雄性C57BL/6小鼠，随机分为3组，每组8只，分别为溶剂对照组(vehicle组)、GLP-1组(30nmol/kg)、PEP6组(30nmol/kg)，均为皮下注射，然后分别在给药后的0.5h、1h、2h、4h、6h、8h、10h、12h给予葡萄糖(1.5g/kg)，在给糖之后的15min检测血糖。
结果如图2所示，PEP6在给药8h后，与对照组相比仍然具有显著性差异(p<0.001)，说明PEP6能够持续作用达到8h之久。
实施例2
本实施例为采用肥胖模型小鼠对PEP6肽进行药效学评价。
本实施例具体内容如下：
1、高脂诱导的肥胖模型小鼠造模
3-4周龄的雄性C57小鼠(购自扬州大学实比较医学中心，许可证号：SCXK(苏)2012-0004)100只，高脂饲料(60kcal％fat，D12492)喂养，造肥胖模型。
选取体重大于40g的成模小鼠，随机分组，共分成四组，分别为溶剂对照组(Vehicle组)、Exendin-4组(阳性对照组)、PEP6组(实验组)、GLP-1组(阳性对照组)，每组10只；皮下注射50nmol/kg/只，注射量0.1ml，早晚各一次。溶剂对照组，皮下注射0.1ml生理盐水。注：Exendin-4即艾塞那肽。
2、PEP6肽对肥胖小鼠进食和体重的影响
从给药开始，每组分别记录初始添食量，隔3-5天检测剩食量，并继续添加新的鼠粮，并记录，依次类推，到11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3的a图所示，PEP6组和Exendin-4阳性对照组具有相同的抑制进食的效果，累计进食量明显少于溶剂组和GLP-1组。
从实验开始起，每周测定小鼠体重，给药前的空腹体重作为给药0周体重，之后方法相同。结果如图3的b图所示，PEP6组能够显著降低肥胖小鼠的体重，其降低体重效果明显优于GLP-1组和Exendin-4组。
3、PEP6肽对肥胖小鼠体脂含量的影响
12周给药结束后，1％戊巴比妥钠50mg/Kg腹腔注射麻醉，配合吸入麻醉剂异氟醚，确保小鼠呼吸缓慢且平稳，T2-MRI：扫描序列：TE(ms)＝10.0，TR(ms)＝1409.0，FOV＝100。进行MRI核磁监测体脂含量，并计算。
结果如图4所示，PEP6组和Exendin-4组均能够降低小鼠脂肪含量，PEP6组降低脂肪含量优于Exendin-4组，存在显著性差异。PEP6组降低小鼠体脂含量的效果显著优于GLP-1组和Exendin-4组。
4、PEP6肽对肥胖小鼠白色脂肪、肝脏的影响
将给药12周后的小鼠处死，留取其白色脂肪组织和肝脏组织，立即放于液氮中保存。取白色脂肪组织和肝脏组织进行HE染色。
结果如图5所示，PEP6组小鼠的脂肪细胞直径明显比较小，Exendin-4给药组小鼠次之，对照组和GLP-1组小鼠脂肪细胞明显较大；对照组和GLP-1组小鼠的肝脏组织脂肪空泡明显，Exendin-4给药组小鼠可观察到少数空泡，PEP6组小鼠基本没有脂肪空泡。说明PEP6组小鼠能够明显降低脂肪细胞大小，减少肝脏组织脂肪空泡(脂肪肝的表征)。
5、PEP6肽对肥胖小鼠血清指标的影响
给药12周后，眼眶取血，静置收集血清，分别检测高密度脂蛋白(HDL)、甘油三酯(TG)、胆固醇(t-CHO)、低密度脂蛋白(LDL)含量。
结果如图6所示，PEP6组小鼠的高密度脂蛋白(HDL)的含量显著增高；PEP6组小鼠的甘油三酯(TG)、胆固醇(t-CHO)、低密度脂蛋白(LDL)的含量均降低。说明PEP6能够优于GLP-1组和Vehicle组，显著改善肥胖小鼠的血清指标。
6、PEP6肽对肥胖小鼠耗氧量的影响
给药12周后，将小鼠放在代谢笼中检测其代谢指标。
结果如图7所示，PEP6组小鼠的耗氧量和能量消耗显著高于GLP-1组和Exendin-4组，说明PEP6可以通过增加基础耗氧量降低小鼠体重。
除上述实施例外，本发明还可以有其他实施方式。凡采用等同替换或等效变换形成的技术方案，均落在本发明要求的保护范围。
序列表
<110> 平顶山学院
<120> 长效GLP-1类似物多肽的减肥用途
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 67
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
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Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly Pro
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Gly His Ala Asp Gly Thr Phe Thr Ser Asp Tyr Ser Ser Tyr Leu Glu
35 40 45
Gly Gln Ala Ala Lys Lys Phe Ile Gln Trp Leu Val Asn Gly Glu Gly
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Pro Pro Pro
65
Claims (8)
1.一种长效GLP-1类似物多肽用于制备治疗或预防肥胖的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
2.一种长效GLP-1类似物多肽用于制备降低体脂含量的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
3.一种长效GLP-1类似物多肽用于制备治疗或预防脂肪肝病的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
4.一种长效GLP-1类似物多肽用于制备降低脂肪细胞大小和/或减少肝脏组织脂肪空泡的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
5.一种长效GLP-1类似物多肽用于制备增高高密度脂蛋白且降低甘油三酯、胆固醇以及低密度脂蛋白的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
6.一种长效GLP-1类似物多肽用于制备增加基础耗氧量的药物或药物组合物的用途，所述多肽的氨基酸序列如SEQ ID No.1所示。
7.根据权利要求1至6任一项所述的用途，其特征是，所述多肽为多肽自身或其药用盐。
8.根据权利要求1至6任一项所述的用途，其特征是，所述药物组合物包括药物载体。
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| CN109134661A (zh) * | 2017-06-19 | 2019-01-04 | 中国药科大学 | 长效降糖调脂多肽及其用途 |
| CN110151980A (zh) * | 2019-06-30 | 2019-08-23 | 中国药科大学 | Glp-1受体激动剂融合蛋白在制备预防或治疗高血脂药物中的应用 |
| CN111032864A (zh) * | 2017-06-19 | 2020-04-17 | 瑞典孤儿比奥维特鲁姆有限公司 | 具有半衰期延长多肽的融合蛋白 |
| CN111138552A (zh) * | 2020-01-15 | 2020-05-12 | 中国药科大学 | 一种降脂多肽及其制药应用 |
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| CN109134661A (zh) * | 2017-06-19 | 2019-01-04 | 中国药科大学 | 长效降糖调脂多肽及其用途 |
| CN111032864A (zh) * | 2017-06-19 | 2020-04-17 | 瑞典孤儿比奥维特鲁姆有限公司 | 具有半衰期延长多肽的融合蛋白 |
| CN110151980A (zh) * | 2019-06-30 | 2019-08-23 | 中国药科大学 | Glp-1受体激动剂融合蛋白在制备预防或治疗高血脂药物中的应用 |
| CN111138552A (zh) * | 2020-01-15 | 2020-05-12 | 中国药科大学 | 一种降脂多肽及其制药应用 |
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