CN110305206A - 一类双靶点多肽化合物及其在制备治疗糖尿病和以其为特征的病症的药物中的应用 - Google Patents
一类双靶点多肽化合物及其在制备治疗糖尿病和以其为特征的病症的药物中的应用 Download PDFInfo
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Abstract
一类双靶点多肽化合物及其在制备治疗糖尿病和以其为特征的病症的药物中的应用。本发明属于生物医药化学领域,涉及一类对胰高血糖素样肽‑1受体(Glucagon‑like peptide‑1 receptor,GLP‑1R)和胰高血糖素受体(Glucagon receptor,GCGR)两种受体同时具有激动效应的双靶点多肽化合物与用途。本发明提供的双靶点激动剂‑多肽化合物,可以同时激动GLP‑1R和GCGR两种膜受体,从而具有有效调控集体糖稳态和能量代谢的能力,可以显著降低血糖浓度。同时,本发明提供的多肽化合物生物学活性高,副作用低;在药物的药代实验中显示出显著的稳定性;易于放大生产,成本低,具有用于制备治疗糖尿病药物的潜力。
Description
技术领域
本发明属于生物医药化学领域,涉及一类对胰高血糖素样肽-1受体(Glucagon-like peptide-1receptor,GLP-1R)和胰高血糖素受体(Glucagon receptor,GCGR)两种受体同时具有激动效应的双靶点多肽化合物。本发明同时还涉及该化合物在制备治疗糖尿病及肥胖症等糖尿病相关并发症的药物中的应用。
背景技术
糖尿病(diabetes mellitus,DM)是由多种病因引起的代谢紊乱,其特点是慢性高血糖,伴有胰岛素分泌缺陷或胰岛素作用障碍,导致碳水化合物、脂肪、蛋白质代谢紊乱,造成多种器官的慢性损伤、功能障碍衰竭。近年来,糖尿病已成为继心脑血管疾病、恶性肿瘤之后,世界范围内另一种严重危害人类健康的慢性疾病。而且,糖尿病的全球患病率正呈现快速增加的趋势。据国际糖尿病联盟(IDF)估算,糖尿病的全球患病率会由2015年的4.15亿人增至2040年的6.42亿人。当前,我国已经成为了世界第一糖尿病大国,约有1.1亿糖尿病患者。世界卫生组织(WHO)估计,2005到2015年间中国由于糖尿病及相关心血管疾病导致的经济损失达5577亿美元。随着经济的持续发展和人们饮食结构的改变,我国糖尿病患者的数目还在继续快速增长。近年多项调查表明:无论是欧美发达国家,还是在包括中国在内的发展中国家,糖尿病控制状况均不容乐观。市场上亟需切实有效的糖尿病治疗药物。
传统的治疗糖尿病的药物主要有胰岛素类药物、胰岛素促泌剂、胰岛素增敏剂、减少碳水化合物吸收的药物以及影响其他作用靶点的药物。近年来,学术界和制药公司对糖尿病发病机制及治疗方案的研究不断深入,为治疗糖尿病的药物开发提供了新的药物靶标,上市了一批多肽类药物。相较于小分子化学药物和大分子蛋白药物,多肽化合物药物具有其独特的优点:1)多肽药物与一般小分子药物相比,活性更高、用药剂量更小、毒副作用更低。而且,多肽药物的代谢终产物为氨基酸,毒副作用小或无。2)多肽药物多数源于内源性多肽或其它天然肽,结构清楚,作用机制明确,成药性好。3)多肽药物与外源蛋白质相比,免疫原性较低,而且可以化学合成,产品纯度高,质量可控。2005年以来上市的胰高血糖素样肽-1(Glucagon-like peptide-1,GLP-1)类似物,通过激动GLP-1受体(GLP-1R)调节人体的糖代谢,为糖尿病的治疗提供了新的用药选择。
与GLP-1R单靶点激动剂相比,能同时激动GLP-1R/GCGR的双重激动剂多肽化合物已被证实具有更好的降糖、降脂、降体重的协同效应,在糖尿病治疗上具有明显优势。
因此,研发更有效更安全的GLP-1R/GCGR双靶点激动剂多肽药物是目前研制治疗糖尿病药物的焦点。
发明内容
本发明提供了一种具有胰高血糖素样肽-1受体(Glucagon-like peptide-1receptor,GLP-1R)和胰高血糖素受体(Glucagon receptor,GCGR)双靶点激动效应的多肽化合物及其在制备治疗糖尿病药物中的应用。发明人经过大量的实验研究证明:本发明中所描述的具有胰高血糖素样肽-1受体(Glucagon-like peptide-1receptor,GLP-1R)和胰高血糖素受体(Glucagon receptor,GCGR)双靶点激动效应的多肽化合物具有降血糖、降血脂、降体重及促胰岛素活性的活性,具有用于糖尿病等疾病治疗的潜力。
本发明提供了可同时激动GLP-1R/GCGR的一类双靶点激动剂的结构。本发明提供的GLP-1R/GCGR双靶点激动剂为同源性多肽。本发明中的同源性多肽是指,多肽本来具有GLP-1、OXM、glucagon或Exenatide等多肽的全部或部分氨基酸序列,但其中一个或多个氨基酸残基在本发明中已被不同氨基酸残基取代,并且所得到的多肽可用于实施本发明。
本发明的目的通过以下技术方案予以实现:
一类具有胰高血糖素样肽-1受体和胰高血糖素受体双靶点激动活性的多肽化合物,母体肽氨基酸序列如下:
His-D-Ser-Gln-Xaa4-Thr-Phe-Xaa7-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2
Xaa4=Gly或Ala;
Xaa7=Thr或Ser。
优选地,所述母体肽氨基酸序列的第13位Lys侧链连接的亲脂性取代基为如下结构:
优选地,母体肽中,氨基酸序列选自PEPT#1,PEPT#2,PEPT#3,PEPT#4中的一种或多种:其中,PEPT#1,PEPT#2,PEPT#3,PEPT#4的氨基酸序列依次为:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2;
His-D-Ser-Gln-Gly-Thr-Phe-Ser-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2;
His-D-Ser-Gln-Ala-Thr-Phe-Thr-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2;
His-D-Ser-Gln-Ala-Thr-Phe-Ser-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2。
本发明同时提供所述多肽化合物在制备治疗糖尿病药物中的应用。
优选地,所述多肽化合物作为一类胰高血糖素样肽-1受体和胰高血糖素受体的双靶点激动剂,制备用于预防,或直接或间接治疗糖尿病或以其为特征的病症的药物。
本发明提供的双靶点激动剂可以同时激动GLP-1R和GCGR两种膜受体(表2),从而具有有效调控集体糖稳态和能量代谢的能力,可以显著降低血糖浓度(图1),具有用于制备治疗糖尿病药物的潜力。本发明提供的此类多肽化合物还可引起摄食量降低和/或能量消耗升高,从而防止体重增长或促进体重减轻。
独立于其对体重的作用,本发明化合物可对循环胆固醇水平具有有益作用(能够降低循环LDL水平以及提高HDL/LDL比值)。因此,本发明多肽可用于直接或间接治疗由体重超重所引起的或者以其为特征的任何病症,例如治疗和/或预防肥胖症、病态肥胖症、肥胖症相关炎症、肥胖症相关的胆囊疾病、肥胖症引起的睡眠呼吸暂停。本发明化合物还可用于预防代谢综合征、高血压、致动脉粥样化性异常脂肪血症、动脉粥样硬化、动脉硬化、冠心病或中风。本发明多肽在这些病症中的作用可以是由多肽对体重的作用所致或与之相关,或者可以独立于其对体重的作用。
本发明的药物组合物适用于各种给药方式,包括但不限于口服给药,经皮给药,静脉给药,肌肉内给药,局部给药等。根据所采用的给药方式,可将本发明的多肽药物组合物制成各种合适的剂型,其中包含至少一种有效剂量的本发明的多肽和至少一种药学上可接受的药用载体。
适当剂型的实例为片剂、胶囊、糖衣片剂、粒剂、口服溶液和糖浆、用于皮肤表面的油膏和药贴、气雾剂、鼻喷剂、可用于注射的无菌溶液等。含有本发明多肽药物组合物可以制成溶液或者冻干粉末以用于胃肠外给药,在使用前可加入适当溶剂或其他可药用的载体将粉末重新配置,液体配方一般是缓冲液,等渗溶液和水溶液。
本发明药物组物种多肽的用量可以在一个较大范围内变动,本领域技术人员可以根据一些客观的因素如根据疾病的种类,病情严重程度,病人体重,剂型,给药途径等因素很容易的加以确定。
与现有技术相比,本发明具有以下优点及有益效果:
1)生物学活性高,副作用低;
2)在药物的药代实验中显示出显著的稳定性;
3)易于放大生产,成本低。
附图说明
图1:艾塞那肽(Exenatide),化合物PEPT#1-4对肥胖小鼠糖耐量的影响。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
本发明中所用缩写具体含义如下:
GLP-1R为胰高血糖素样肽1受体,GCGR为胰高血糖素受体,GLP-1为胰高血糖素样肽,His为组氨酸,Ser为丝氨酸,D-Ser为D-型丝氨酸,Gln为谷氨酰胺,Gly为甘氨酸,Glu为谷氨酸,Ala为丙氨酸,Thr为苏氨酸,Lys为赖氨酸,Arg为精氨酸,Tyr为酪氨酸,Asp为天冬氨酸,Trp为色氨酸,Phe为苯丙氨酸,IIe为异亮氨酸,Leu为亮氨酸,Pro为脯氨酸,Met为蛋氨酸,Asn为天冬酰胺。
实施例1多肽化合物
表1.本发明实施例中所提供的多肽化合物结构
实施例2.GCGR和GLP-1R体外活性测定
利用cAMP Assay Kit(CISBIO公司)检测本发明描述的多肽化合物PEPT#1-4对胰高血糖素样肽1受体(GLP-1R)和胰高血糖素受体(GCGR)的激动作用,构建剂量效应曲线,定量评价多肽化合物PEPT#1-4的对GLP-1R和GCGR的激动活性。实验以艾塞那肽(Exenatide),胰高血糖素(Glucagon)及胃泌酸调节素(Oxyntomodulin)作为参照品。
实验方法如下:
(1)首先构建用于CRE-荧光素酶系统的,稳定表达人GCGR或GLP-1R的HEK-293细胞。按照每孔98.0L DMEM/10%FBS培养基、5000个细胞接种到384孔板中,过夜培养。
(2)在细胞铺板后的第二天,将待测多肽化合物PEPT#1-4分别制备成从0.005nM到100.0nM的梯度稀释液;将参照物艾塞那肽和胰高血糖素分别制备成从0.005nM到100.0nM的梯度稀释液,将参照物胃泌酸调节素标准品制备从0.01nM到100nM的梯度稀释液。在每孔细胞中,分别加入2.0L不同浓度的待测化合物或参照物,与细胞混合并孵育培养12小时。
(3)在平板的每孔中,加入10.0L荧光素酶试剂,轻轻混匀2分钟后,将平板放入Perkin Elmer读板仪读数。
(4)利用作图软件Prism 5制作化合物浓度效应曲线,计算各化合物的对两种受体的EC50值,具体见表2。
表2.本发明多肽化合物的平均EC50值
结果表明,与胃泌酸调节素相比,本发明多肽化合物对GCGR和GLP-1R两种受体的效力均更高;与艾塞那肽和胰高血糖素相比,本发明多肽化合物对两种受体的激动效力更均衡。
实施例3.基于口服葡萄糖耐受实验(OGTT)评价化合物PEPT#1-4和艾塞那肽(Exenatide)的降血糖活性
实验方法:
(1)将12~16周龄的雄性C57Bl/6J小鼠随机分成6组(每组8只,组间血糖差异不大于1.1mmol/L),分别为正常组、艾塞那肽阳性对照组、受试多肽化合物系列药物组。
(2)试验小鼠采用皮下注射给药,给药剂量为3ug/只小鼠,给药体积为0.1ml/只。正常组给予等体积的溶媒PBS溶液。
(3)给药4h后,获取初始血液样品(禁食血液葡萄糖水平)。
(4)随后,给予每只老鼠灌胃葡萄糖(100mg/ml葡萄糖溶液×20ml),并将动物放回其饲养笼中(t=0)。在30、60、120min时测量血糖。
(5)每两小时重复给予灌胃同样剂量的葡萄糖,跟踪血糖直到8个小时。
(6)使用软件GraphPad Prism处理数据作出血糖变化折线图,并计算曲线下面积得到AUC图。AUC=0.25×(0分钟血糖)+0.5×(30分钟血糖)+0.75×(60分钟血糖+0.5×(120分钟血糖)。
实验结果表明:与载剂(PBS)相比,艾塞那肽在口服葡萄糖耐受实验(OGTT)的第一个时段(1-120min)可以显著降低AUC,而在随后的三个OGTT曲线时段(120-480min),其降低AUC的作用削弱,AUC接近空白对照组。与载剂(PBS)相比,多肽化合物PEPT#1-4在全部四个OGTT时段的AUC均有显著降低,具有长效降糖效果,且多肽化合物PEPT#1-4的降糖效果相互之间不存在显著性差异(图1)。
因此,本说明涉及的多肽化合物PEPT#1-4均具有长效降糖的效果,能够用于预防或直接或间接治疗糖尿病或者以其为特征的病症。
以上以实例方式对本发明进行了说明,尽管未示出,但本发明保护范围内的所有多肽均可实现本发明的技术效果,并且本领域技术人员以本发明进行修改或变形,只要不脱离本发明的精神,均落入本发明所附权利要求的范围内。
Claims (7)
1.一类具有胰高血糖素样肽-1受体和胰高血糖素受体双靶点激动活性的多肽化合物,其特征在于,母体肽的氨基酸序列如下:
His-D-Ser-Gln-Xaa4-Thr-Phe-Xaa7-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2
Xaa4=Gly或Ala;
Xaa7=Thr或Ser。
2.根据权利要求1所述多肽化合物,其特征在于,所述母体肽中氨基酸序列的第13位Lys侧链连接的亲脂性取代基为如下结构:
Lys(PEG2-PEG2-CO(CH2)16CO2H):
。
3.根据权利要求1所述多肽化合物,其特征在于,母体肽中,氨基酸序列选自PEPT#1,PEPT#2,PEPT#3,PEPT#4中的一种或多种:其中,PEPT#1,PEPT#2,PEPT#3,PEPT#4的氨基酸序列依次为:
His-D-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2;
His-D-Ser-Gln-Gly-Thr-Phe-Ser-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2;
His-D-Ser-Gln-Ala-Thr-Phe-Thr-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2;
His-D-Ser-Gln-Ala-Thr-Phe-Ser-Ser-Lys-Glu-Tyr-Arg-Lys(PEG2-PEG2-CO(CH2)16CH3)-Tyr-Leu-Arg-Glu-Gln-Lys-Ala-His-Asp-Phe-Gly-Gly-Trp-Leu-Met-Asn-Thr-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-NH2。
4.一种权利要求1至3中任一所述多肽化合物在制备治疗糖尿病药物中的应用。
5.根据权利要求4所述应用,其特征在于,所述多肽化合物作为一类胰高血糖素样肽-1受体和胰高血糖素受体的双靶点激动剂,制备用于预防,或直接或间接治疗糖尿病或以其为特征的病症的药物。
6.根据权利要求4所述应用,其特征在于,所述药物还包括药学上可接受的药用载体。
7.根据权利要求6所述应用,其特征在于,药物的剂型为片剂、胶囊、糖衣片剂、粒剂、口服溶液、糖浆、用于皮肤表面的油膏和药贴、气雾剂、鼻喷剂、可用于注射的无菌溶液、冻干粉剂。
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