CN110251662A - 一种具有减肥作用的药物 - Google Patents
一种具有减肥作用的药物 Download PDFInfo
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- CN110251662A CN110251662A CN201811521016.1A CN201811521016A CN110251662A CN 110251662 A CN110251662 A CN 110251662A CN 201811521016 A CN201811521016 A CN 201811521016A CN 110251662 A CN110251662 A CN 110251662A
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Abstract
本发明公开了GLP‑1突变体在制备减肥药物中的用途,GLP‑1突变体是在野生型GLP‑1基础上,经过氨基酸位点突变得到,它的氨基酸序列如SEQ ID NO:1所示。本发明GLP‑1突变体,可以有效降低体重和脂体比等指标,可用于肥胖人群减轻体重,应用前景广阔。
Description
技术领域
本发明属于基因工程技术领域,具体涉及GLP-1突变体的用途。
背景技术
随着人们膳食结构和生活方式的改变,肥胖已成为世界范围内的流行病。目前全球范围内超重和肥胖的发生率都呈逐年增加的趋势。特别是我国,近年来超重和肥胖的发生率已接近甚至达到发达国家初期的水平。对于那些 BMI指数高的人群来说,肥胖会引起其他一些疾病发病率的上升,其中最为显著的是糖尿病、心血管疾病和癌症,超重/肥胖严重危害人类的健康。
同时,超重/肥胖是2型糖尿病(Type 2Diabetes Mellitus,T2DM)发生、发展的独立危险因素,两者是相伴相生的疾病状态。研究表明,体质指数每增加1kg/m2,T2DM的患病风险就增加12%;而在T2DM患者中,超重和肥胖症的患病率超过80%。同时,超重和肥胖状态会进一步加重T2DM患者的胰岛素抵抗状态,并大大增加心血管疾病等并发症的发生风险。强化减肥可为 T2DM患者带来明确的收益:减轻胰岛素抵抗状态、修复受损的胰岛β细胞功能、优化血糖控制及改善心血管疾病的相关危险因素等。肥胖与T2DM引发的恶性循环状态,使传统的以“降糖”为核心的治疗模式进入到一个两难的境地,这也使越来越多学者开始关注“减肥”治疗的重要性。
单纯生活方式干预虽然能使肥胖患者的体重下降,但长期疗效并不理想,究其原因,一方面与大部分患者很难严格坚持减肥生活方式有关;另一方面还与大部分传统药物在应用过程中均会不可避免地增加体重有关。
但是,多种减肥药物在带来良好减肥疗效的同时,因存在着严重的安全问题逐步退出市场。目前临床应用的减肥药品主要有1999年批准的奥利司他胶囊,2012年批准的氯卡色林和苯丁胺和托吡酯胶囊,2014年批准的盐酸纳曲酮、安非他酮复方缓释片以及利拉鲁肽注射液。
利拉鲁肽(Liraglutide)是胰高血糖素样肽1(glucagon-likepeptide-1, GLP-1)类似肽,为新型的基于肠促胰素作用的药物。GLP-1类似肽主要通过抑制中枢摄食欲望和抑制胃肠蠕动,增加饱腹感来减少患者对能量的摄入,从而发挥减肥的疗效。利那鲁肽具有葡萄糖浓度依赖性的降糖作用,单药治疗不会导致低血糖。
利拉鲁肽于2009年和2010年分别在美国和欧盟上市用于2型糖尿病 (T2DM)的治疗。2014年和2015年,FDA和欧洲药品管理局批准其作为饮食控制和体育锻炼的补充,用于慢性肥胖的治疗,效果优于市场上的主流减肥药—奥利司他,减肥效果明确,是用于肥胖治疗的首款日用一次的GLP-1类似肽。利拉鲁肽于2011年在中国批准上市。长期试验表明,利拉鲁肽能够有效减轻患者体重,其适应人群是体重指数(BMI)大于或等于30的成年人,或者是BMI为27及以上、伴有T2DM、高血压或高胆固醇等至少一种肥胖并发症的成年人。在人们强烈的减肥欲望与疗效不佳的现有减肥药形成大矛盾的今天,开发GLP-1类似肽类的减肥药也是一个不二的选择。因此,兼具减肥和降血糖双重效益的药物具有十分广阔的市场前景。
但是,目前包括利拉鲁肽在内的GLP-1类似肽为多肽类药物,均需注射给药,直接口服无效,存在用药不便等缺点。但是肥胖人群减重通常需要长期、持续用药。注射给药的方式,使用携带不方便,用药依从性差,还可能存在刺激性和过敏反应等风险,给患者带来巨大的生理和心理痛苦。而口服制剂最符合人们“服”药的习惯,制剂工艺也成熟而简单。因此从改变GLP-1类似肽的给药途径入手,研制用药和携带方便,适用于长期使用的GLP-1类似肽类药物,意义重大。
发明内容
本发明的目的在于提供一种GLP-1突变体及其制备方法和用途。
本发明提供GLP-1突变体在制备减肥药物中的用途,所述GLP-1突变体是在野生型GLP-1基础上,经过氨基酸位点突变得到,它的氨基酸序列如 SEQ ID NO:1所示。
本发明还提供了编码SEQ ID NO:1所示氨基酸序列的核苷酸序列在制备减肥药物中的用途;优选地,序列如SEQ ID NO:2所示。
本发明还提供了重组载体在制备减肥药物中的用途,其特征在于:所述重组载体包含前述核苷酸序列;进一步地,所述重组载体是重组原核载体;更进一步地,所述原核载体为pGEX质粒或者pMG36e载体。
本发明还提供了重组菌在制备减肥药物中的用途,其特征在于:所述重组菌类包含前述的重组载体;进一步地,所述重组菌为重组大肠杆菌Nissle 1917或者重组乳酸菌。
本发明还提供了一种减肥药物,其特征在于:它含有前述GLP-1突变体、前述核苷酸序列、前述重组载体和/或前述重组菌。
本发明还提供了一种减肥的药物,其特征在于:它以氨基酸序列如SEQ ID NO:1所示GLP-1突变体、SEQ ID NO:2所示核苷酸序列、包含SEQ ID NO:2所示的核苷酸序列的重组载体和/或包含SEQ ID NO:2所示核苷酸序列的重组菌为有效成分。
本发明还提供了一种减肥的保健食品,其特征在于:它以氨基酸序列如SEQ IDNO:1所示GLP-1突变体、SEQ ID NO:2所示核苷酸序列、包含 SEQ ID NO:2所示的核苷酸序列的重组载体和/或包含SEQ ID NO:2所示核苷酸序列的重组菌为有效成分。
与天然的GLP-1相比,本发明GLP-1突变体,减小了DPP-Ⅳ的降解作用。而且本发明构建的含有GLP-1突变体的重组益生菌,可制备成多种类型的固体及液体制剂实现口服给药,避免患者长期注射用药的痛苦;同时,人体服用后,该基因工程益生菌可以在人体肠道中存活定植,成为功能性的体内生物反应器,持续产生并分泌GLP-1突变体多肽,从而起到持续控制体重的作用,应用前景良好。
国内外对药物改良的思路中口服给药是最理想的给药途径,但口服给药需要解决GLP-1类似肽在胃肠道中被容易被胃酸、酶破坏和难以吸收的问题,以提高其生物利用度,降低个体差异。本发明从改变GLP-1类似肽的现有给药途径入手,绕过传统药剂学手段,创造性地利用基因工程技术,将外源性基因转化入益生菌中,使得该新型基因工程益生菌可分泌GLP-1类似肽,并且该基因工程菌益生菌还可与益生元(如低聚果糖、菊粉、低聚半乳糖、低聚异麦芽糖、低聚果糖等)、膳食纤维或植物提取物等混合制备成多种类型的固体及液体制剂实现该多肽类药物的口服给药。本发明可以单独形成制剂,也可作为添加剂加入其它药品或食品中用于减肥、降脂。服用后,该基因工程益生菌可以在人体肠道中存活定植,持续产生并分泌GLP-1类似肽,成为功能性的体内生物反应器,从而起到治疗肥胖症的作用。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1突变体GM的SDS-PAGE及WB检测结果。
图2突变体GM转化大肠杆菌Nissle1917对小鼠体重和体重增长值的影响,与正常组相比Δp<0.05,ΔΔp<0.01;与模型组相比*p<0.05,**p <0.01。
图3突变体GM转化大肠杆菌Nissle1917对小鼠摄食量的影响,与正常组相比Δp<0.05,ΔΔp<0.01;与模型组相比*p<0.05,**p<0.01。
图4突变体GM转化大肠杆菌Nissle1917对小鼠空腹血糖及血糖浓度变化曲线下面积的影响,与正常组相比Δp<0.05,ΔΔp<0.01;与模型组相比*p<0.05,**p<0.01。
图5突变体GM转化大肠杆菌Nissle1917对小鼠肾脏周围脂肪组织重量及脂体比的影响,与正常组相比Δp<0.05,ΔΔp<0.01;与模型组相比*p <0.05,**p<0.01。
图6突变体GM转化大肠杆菌Nissle1917对小鼠睾丸(卵巢)周围脂肪组织重量及脂体比的影响,与正常组相比Δp<0.05,ΔΔp<0.01;与模型组相比*p<0.05,**p<0.01。
图7突变体GM转化大肠杆菌Nissle1917对小鼠肝脏重量的影响,与正常组相比Δp<0.05,ΔΔp<0.01;与模型组相比*p<0.05,**p<0.01。
具体实施方式
下面以实施例作进一步说明,但本发明不局限于这些实施例。
本发明所用的实验试剂与仪器如下:
pGEX-4T-1、pMG36e、pET32a、E.coli TOP10及E.coli BL21(DE3)、大肠杆菌Nissle1917、乳酸杆菌、乳酸乳球菌等菌株与质粒由成都里来生物科技有限公司和重庆医科大学生物化学与分子生物学教研室提供。SPF级昆明小鼠由成都达硕实验动物有限公司提供。T4连接酶、Taq普通酶、SalⅠ、 BamHⅠ、蛋白质Marker、DNA Marker、Plasmid Mini kit I、Cycle-Pure Kit、胶回收试剂盒、IPTG、红霉素、BCA蛋白浓度测定试剂盒、PMSF等试剂(均为市售)。
实施例1本发明对GLP-1原始序列的改造
从GLP-1原始序列出发,改造设计突变体多肽序列,通过化学合成(中肽生化),获得纯度高达85%的多肽产物。多肽序列如下:
GLP-1片段(7-37aa):HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG
GM(SEQ ID NO:1):HHEGTFTSDVSSYLEGQAAKKFIAWLVRGGKKKKKYGRKK RRQRRREF
GM是在GLP-1原始序列的基础上,将GLP-1第8位丙氨酸突变为组氨酸, 27位的谷氨酸突变为赖氨酸,34位的赖氨酸突变为精氨酸,36位的精氨酸突变为甘氨酸,37位的甘氨酸突变为赖氨酸,并且末端加入一段序列。
GLP-1原始序列与突变体GM的区别如表1所示。
表1GLP-1及突变体GM的序列比较
实施例2突变体GM转化大肠杆菌Nissle1917
1、在GLP-1突变体GM的序列前加入一段信号肽序列、在3’-端加入HIV 穿膜肽序列和6个His-tag序列,构建出能够分泌表达和具有穿过细胞膜能力的GLP-1突变体,其核苷酸序列如SEQ ID NO:2所示。
SEQ ID NO:2:
atgaaaaagaacatcgcattcctcctggcatctatgtttgttttctctatcgctaccaacgcttacgctggatcccaccacgagggcaccttca cctccgacgtgtcctcctacctggagggccaggccgccaagaagttcatcgcctggctggtgcgcggcggcaagaagaagaagaagt acggccgcaagaagcgccgccagcgccgccgcctcgaggacgacgacgacaagcaccatcaccatcaccattaa
2、将SEQ ID NO:3所示的核苷酸序列克隆到大肠杆菌Nissle1917表达载体pGEX的BamHI和SalI位点,获得pGEX-GLP-1GM载体,测序正确后转化大肠杆菌E.coli BL21(DE3)中,目的片段大小约为12KD。经含镍磁珠纯化后 Western blot鉴定表达结果正确,结果如图1所示。可见,本发明成功表达了 GLP-1突变体蛋白。
3、将pGEX-GLP-1GM表达载体转化到大肠杆菌Nissle 1917中,经PCR和测序鉴定pGEX-GLP-1GM转化成功。取重组大肠杆菌Nissle 1917,接种到添加有终浓度为200μg/ml的红霉素的LB培养基上,37℃、250r/min摇床培养至培养至每毫升活菌不低于1010。
实施例3突变体GM转化大肠杆菌Nissle1917制剂的制备
1、突变体GM转化大肠杆菌Nissle1917口服液的制备
添加有终浓度为200μg/ml的红霉素抗性LB液体培养基蒸汽灭菌后,取经 PCR验证及诱导表达实验鉴定的基因稳定转化的大肠杆菌Nissle1917(实施例2 制备)接种,37℃、250r/min摇床培养至OD600值达到0.8~1.0后,离心5min 收获细菌,用生理盐水洗涤2次,离心收集菌体沉淀后加终浓度为2%(w/v) 的L-阿拉伯糖溶液或20%的低聚果糖溶液重悬细菌,配制成每毫升不低于108活菌的新鲜菌液,分装后于4℃冰箱冷藏保存。
2、突变体GM转化大肠杆菌Nissle1917/冻干粉的制备
取上述方法收获的细菌沉淀,加终浓度为20%(w/v)的低聚果糖重悬细菌,再加入终浓度为15%(w/v)的甘油、10%(w/v)的脱脂奶粉、3%(w/v) 的乳糖和3%(w/v)的海藻糖,配制成每克不低于1010活菌的混合液体,分装后置于冷冻干燥机上冻干,封口后4-8℃冰箱保存。
3、突变体GM转化大肠杆菌Nissle1917干燥粉剂的制备
取上述方法收获的细菌沉淀,加终浓度为20%(w/v)的低聚果糖重悬细菌,再加入终浓度为10%(w/v)的脱脂奶粉、3%(w/v)的乳糖和3%(w/v) 的海藻糖,配制成每克不低于1010活菌的混合液体,分装后置于真空干燥仪上烘干,最高温度不超过40℃,封口后4-8℃冰箱保存。
实施例4突变体GM转化大肠杆菌Nissle1917减肥作用研究
1、实验动物
SPF级昆明小鼠,体重20-25g,购自成都达硕实验动物有限公司。合格证号:SCXK(川)2015-030。动物接收后进行检疫及适应性观察3天,合格后开始实验。动物自由饮水摄食,温度(20±2)℃,湿度(60±5)%,12h光照周期。
2、实验动物分组
实验动物随机分为:正常组、模型组、重组大肠杆菌Nissle1917(实施例 2制备)高中低剂量组,每组10只动物。
3、实验动物造模及给药方法
正常组喂食普通饲料,其余四组喂食高脂高糖饲料(饲料配方为:普通饲料67%,蔗糖20%,猪油10%,胆固醇2%,胆酸钠1%)。试验动物每天自由进食及饮水。重组大肠杆菌Nissle1917高中低剂量组分别灌胃活菌数为1010、 109、108CFU菌液各0.3ml,模型组灌胃等体积灭菌生理盐水,每日一次,分别在第四周及第八周取材测定。
4、检测指标
(1)体重:每周固定时间测定实验动物体重,并计算体重增长值。
(2)摄食量:每周固定时间测定每组实验动物的给食量和剩食量,计算摄食量。
(3)空腹血糖及口服糖耐量(OGTT)测定:第八周,动物禁食12h后称取体重测定空腹血糖后,每只小鼠一次性灌胃浓度为50%的葡萄糖溶液3g/kg,灌胃葡萄糖后30min、60min、120min、180min尾尖取血采用三诺血糖仪(GA-3 型)测定各时间点血糖值,并计算曲线下面积(AUC)。
(4)体内脂肪重量、脂体比及肝脏重量测定:实验结束后,处死动物,剥离肝脏、肾周脂肪组织和睾丸(卵巢)周围脂肪组织并称重。分别计算肾周脂肪组织和睾丸(卵巢)周围脂肪组织与体重的比值即脂体比。同时剥离肝脏,称取肝脏重量。
5、实验结果
(1)体重及体重增长值
如图2所示,模型组体重及体重增长值较正常组均显著升高(p<0.05)。与模型组相比,四周时菌液高中低剂量组均可显著降低实验动物的体重及体重增长值(p<0.05),八周时菌液高中剂量组可显著降低实验动物的体重及体重增长值(p<0.05)。
(2)摄食量
如图3所示,与模型组相比,菌液高中低剂量组均可显著降低实验动物的摄食量(p<0.05)。与正常组相比,菌液高中低剂量组的摄食量无显著性差异(p>0.05)。
(3)血糖和口服糖耐量
如图4所示,各组间空腹血糖无显著性差异(p>0.05)。灌胃葡萄糖溶液后,除正常组外,各组血糖均显著升高。计算各组血糖浓度AUC,与模型组相比,菌液高中剂量组均可显著降低实验动物糖耐量试验的AUC(p<0.05)。
(4)体内脂肪质量及脂体比
如图5所示,模型组的肾脏周围脂肪组织及脂体比较正常组均显著升高(p <0.05)。与模型组相比,第四周时,菌液高剂量组可显著降低实验动物的肾脏周围脂肪组织及脂体比(p<0.05);第八周时,菌液高中剂量组均可显著降低实验动物的肾脏周围脂肪组织及脂体比(p<0.05)。
如图6所示,模型组的睾丸(卵巢)周围脂肪组织及脂体比较正常组均显著升高(p<0.05)。与模型组相比,第四周时菌液高剂量组可显著降低实验动物的睾丸(卵巢)周围脂肪组织及脂体比(p<0.05);第八周时菌液高中剂量组均可显著降低实验动物的睾丸(卵巢)周围脂肪组织及脂体比(p<0.05)。
(5)肝脏重量
如图7所示,模型组的肝脏组织重量比较正常组均显著升高(p<0.05)。与模型组相比,菌液高剂量组可显著降低实验动物的肝脏重量(p<0.05)。
上述结果表明,突变体GM转化大肠杆菌Nissle1917可抑制实验小鼠的食欲,减少能量吸收;显著降低实验小鼠的体重、体内脂肪含量、脂体比和肝脏的重量,具有十分明显的减肥降脂的作用。同时该转化大肠杆菌Nissle1917 还可显著降低口服糖耐量试验中血糖变化的曲线下面积,具有一定的降低血糖的趋势。
实施例5突变体GM转化乳酸菌
1、突变体GM转化乳酸菌
(1)将GLP-1GM,即SEQ ID NO:2所示的核苷酸序列构建到乳酸菌表达载体pMG36e质粒上SalI和HindIII位点,电转化乳酸杆菌后,挑取重组乳酸杆菌的单菌落,培养后提取质粒,PCR检验和测序检测GLP-1GM基因存在于该受体菌中。
(2)将上述的重组乳酸菌接种到添加有终浓度为20μg/ml的红霉素的 MRS培养基上,30℃静置培养至OD600值达到0.8~1.0时,离心,弃上清,取菌体,备用。
实施例6突变体GM转化乳酸菌制剂的制备
1、突变体GM转化乳酸菌口服液的制备
添加有终浓度为20μg/ml的红霉素的MRS液体培养基蒸汽灭菌,取经PCR 验证及诱导表达实验鉴定的基因稳定转化的乳酸菌(实施例5制备)接种,30℃静置培养至OD600值达0.8~1.0时,离心,弃上清,取菌体沉淀加终浓度为2% (w/v)的L-阿拉伯糖溶液或20%的低聚果糖溶液重悬细菌,配制成每毫升不低于1010活菌的新鲜菌液,分装后于4℃冰箱冷藏保存。
2、突变体GM转化乳酸菌冻干粉的制备
方法与例4相同。
3、突变体GM转化乳酸菌干燥粉剂的制备
方法与例4相同。
天然的GLP-1相比,本发明GLP-1突变体,减小了DPP-Ⅳ的降解作用。而且本发明构建的含有GLP-1突变体的重组益生菌,可以起到持续控制体重的作用,应用前景良好。
SEQUENCE LISTING
<110> 四川利通科创生物医药科技有限公司
<120> 一种具有减肥作用的药物
<130> GY848-18P1764
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 48
<212> PRT
<213> Artificial Sequence
<220>
<223> GM
<400> 1
His His Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly
1 5 10 15
Gln Ala Ala Lys Lys Phe Ile Ala Trp Leu Val Arg Gly Gly Lys Lys
20 25 30
Lys Lys Lys Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Glu Phe
35 40 45
<210> 2
<211> 255
<212> DNA
<213> Artificial Sequence
<220>
<223> GLP-1突变体GM
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atgaaaaaga acatcgcatt cctcctggca tctatgtttg ttttctctat cgctaccaac 60
gcttacgctg gatcccacca cgagggcacc ttcacctccg acgtgtcctc ctacctggag 120
ggccaggccg ccaagaagtt catcgcctgg ctggtgcgcg gcggcaagaa gaagaagaag 180
tacggccgca agaagcgccg ccagcgccgc cgcctcgagg acgacgacga caagcaccat 240
caccatcacc attaa 255
<210> 3
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<212> PRT
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<400> 3
His Ala 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
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Claims (10)
1.GLP-1突变体在制备减肥药物中的用途,其特征在于:GLP-1突变体是在野生型GLP-1基础上,经过氨基酸位点突变得到,它的氨基酸序列如SEQ ID NO:1所示。
2.编码SEQ ID NO:1所示氨基酸序列的核苷酸序列在制备减肥药物中的用途。
3.根据权利要求2所述的用途,其特征在于:优选地,序列如SEQ ID NO:2所示。
4.重组载体在制备减肥药物中的用途,其特征在于:所述重组载体包含权利要求所示2的核苷酸序列。
5.根据权利要求4所述的用途,其特征在于:所述重组载体是重组原核载体。
6.根据权利要求5所述的用途,其特征在于:所述原核载体为pGEX质粒或者pMG36e载体。
7.重组菌在制备减肥药物中的用途,其特征在于:所述重组菌类包含权利要求3所述的重组载体。
8.根据权利要求7所述的用途,其特征在于:所述重组菌为重组大肠杆菌Nissle 1917或者重组乳酸菌。
9.一种减肥的药物,其特征在于:它以氨基酸序列如SEQ ID NO:1所示GLP-1突变体、SEQ ID NO:2所示核苷酸序列、包含SEQ ID NO:2所示的核苷酸序列的重组载体和/或包含SEQ ID NO:2所示核苷酸序列的重组菌为有效成分。
10.一种减肥的保健食品,其特征在于:它以氨基酸序列如SEQ ID NO:1所示GLP-1突变体、SEQ ID NO:2所示核苷酸序列、包含SEQ ID NO:2所示的核苷酸序列的重组载体和/或包含SEQ ID NO:2所示核苷酸序列的重组菌为有效成分。
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