CN106866814B - Dpp-4抑制剂 - Google Patents
Dpp-4抑制剂 Download PDFInfo
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- CN106866814B CN106866814B CN201710090588.8A CN201710090588A CN106866814B CN 106866814 B CN106866814 B CN 106866814B CN 201710090588 A CN201710090588 A CN 201710090588A CN 106866814 B CN106866814 B CN 106866814B
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Abstract
本发明提供一种DPP‑4抑制剂,该DPP‑4抑制剂以式(1):Xe‑Pro/Ala/Hyp‑Xa‑Xb‑Xc‑Xd(式中,Xe表示等电点为5.9~6.3的氨基酸残基,Pro/Ala/Hyp表示Pro、Ala或Hyp,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly、Pro或缺失,Xc表示Pro、Ala或缺失,Xd表示氨基酸残基或缺失。)所示的肽作为有效成分。该抑制剂通过增强肠促胰岛素的作用,可以期待降低血糖值的作用,可以用作糖尿病治疗药,此外,通过对免疫系统等发挥作用,可用于皮肤疾病的治疗等。
Description
本申请为2012年11月2日提交的申请号为201280054376.X且发明名称为“DPP-4抑制剂”的专利申请的分案申请。
技术领域
本发明涉及包含2~6个氨基酸的特定序列的肽的二肽基肽酶4抑制剂(以下,只称作DPP-4抑制剂)。
背景技术
糖尿病是引起高血糖、糖尿、体蛋白的解体、酮病、酸中毒等全身性代谢障碍的慢性疾病。通常,糖尿病大致分为以下两种类型:胰腺的β细胞因为某种原因被破坏,调节血糖值的胰岛素枯竭的1型;以及血中虽然存在胰岛素,但胰岛素的作用差,或者来自胰腺的β细胞的胰岛素分泌量减少,其结果,血糖值的调节功能不全的2型。
近年来,作为调节血糖值的激素,身为消化道激素之一的肠促胰岛素受到关注。肠促胰岛素是随着食物的摄取由消化道分泌、并与胰β细胞发生作用以促进胰岛素分泌的激素的总称,已知有葡萄糖依赖性胰岛素分泌刺激多肽(GIP:glucose-dependentinsulinotropic polypeptide)和胰高血糖素样肽-1(GLP-1:glucagon-like peptide-1)这两种。分泌的肠促胰岛素与胰腺β细胞表面的受体结合,通过胰岛素分泌促进和胰高血糖素的分泌抑制,显示出降低血糖值的作用。肠促胰岛素的胰岛素分泌促进作用依赖于血中葡萄糖浓度,只有在一定浓度以上的葡萄糖存在下才得以体现。即,通过现有的治疗方法即胰岛素直接给药,出现所担心的低血糖的危险性小,可以期待着安全地纠正饭后高血糖。实际上,已知通过静脉对2型糖尿病患者持续给予作为肠促胰岛素之一的GLP-1,可促进胰岛素分泌,血糖控制得到明显改善,显示出GLP-1补充疗法的有效性。
另一方面,GLP-1被生物体内广泛存在的二肽基肽酶4(EC3.4.14.5,以下只称作DPP-4。)快速分解。因此,作为糖尿病治疗方法,新开发了抑制DPP-4的活性以持续增强内源性GLP-1的作用的药物。需要说明的是,DPP-4虽然在T细胞等免疫系细胞表面作为CD26在细胞膜上表达,但作为可溶性蛋白还存在于血液中,是将GLP-1灭活的丝氨酸蛋白酶。其对从N末端起第2位具有Pro或Ala的生理活性肽具有特异性作用,使二肽从N末端游离出来。
基于这样的DPP-4的作用,有包含从N末端起第2位配列有Pro的3~12个氨基酸的肽的DPP-4抑制剂(专利文献1)。该DPP-4抑制剂是将奶酪悬浮于水性溶剂中,之后除去不溶性物质后得到的水溶性组分中所含的肽,经口摄取混合有该肽的饮品时,在生物体内能够降低血糖值。专利文献1中记载的DPP-4抑制剂是由天然物质得到的,所以毒性低、安全性高。
另外,还有由乳蛋白水解物构成、且刺激GLP-1的分泌、以及具有DPP-4抑制作用的肽(专利文献2)。专利文献2中公开的肽优选2~8个氨基酸的长度、且包含Pro作为第二N末端残基的肽。在实施例中,作为某乳蛋白水解物,评价了500~2000Da的肽组合物的DPP-4抑制效果,但它们的组成或肽序列尚不明确。
而且,还有含有来自饮食用原材料的调制物作为有效成分的DPP-4抑制剂(专利文献3)。该DPP-4抑制剂含有固体浓度为3.5mg/ml以下、DPP-4抑制率为60%以上的来自饮食用原材料的调制物作为有效成分。在专利文献3的实施例中,评价了以绿豆、大豆、胶原蛋白、海藻、茶、核桃、甜茶、石榴、葡萄籽等为来源的肽的DPP-4抑制率。
进一步,还以来自胶原蛋白或明胶的、用Gly-X-Y-(Gly-Z-W)n(式中,n表示0~4的整数,X表示Pro或Leu,Y、Z和W各自独立表示相同或不同的任意的氨基酸残基(其中,Gly除外)。)表示的肽作为DPP-4抑制剂(专利文献4)。在实施例中,通过高效液相色谱法分级市售的胶原蛋白肽,鉴定了DPP-4抑制活性优异的组分的肽序列。
另一方面,作为DPP-4抑制剂的作用,已知其抑制T淋巴球的增殖(非专利文献1)。非专利文献1指出:通过DPP-4抑制剂能够缓和自身免疫性脊椎炎、多发性硬化症、关节炎、风湿病等自身免疫疾病。另外,由于DPP-4与HIV-1对CD4阳性T细胞的感染促进有关,所以还有报道称:通过DPP-4抑制剂和其他药物的联用,可以期待防御HIV-1的感染(非专利文献2)。而且,还有报道称:由于皮肤细胞表达DPP-4,所以DPP-4抑制剂对皮脂腺细胞或表皮细胞的增殖或分化或细胞因子的产生有影响(非专利文献3)。使用DPP-4抑制剂抑制被痤疮丙酸杆菌刺激的T淋巴细胞的增殖,引起成纤维细胞的TGFβ的表达抑制、增殖抑制、基质产生抑制,其结果暗示:使用DPP-4抑制剂,能够治疗青春痘、干癣、瘢痕疙瘩。
现有技术文献
专利文献
专利文献1:日本特开2007-39424号公报
专利文献2:日本特表2009-517464号公报
专利文献3:日本特开2010-13423号公报
专利文献4:国际公开第2008/066070号
非专利文献
非专利文献1:Role of dipeptidyl peptidase IV(DP IV)-like enzymes in Tlymphocyte activation:investigations in DP IV/CD26-knockout mic,Clin Chem LabMed.2009;47(3):268-74.
非专利文献2:Inhibition of human immunodeficiency virus type1infection in a T-cell line(CEM)by new dipeptidyl-peptidase IV(CD26)inhibitors.Res Virol.1997Jul-Aug;148(4):255-66.
非专利文献3:The ectopeptidases dipeptidyl peptidase IV(DP IV)andaminopeptidase N(APN)and their related enzymes as possible targets in thetreatment of skin diseases.Front Biosci.2008Jan 1;13:2364-75.
发明内容
发明所要解决的课题
上述专利文献1~4中记载的DPP-4抑制剂均以奶酪或乳蛋白、其他饮食用原材料等天然物质为原料,所以安全性优异,但人们希望开发抑制效果更强的DPP-4抑制剂。
即,专利文献1或专利文献2只限定于特定的肽序列,其他序列中的DPP-4抑制效果尚不明确。另外,专利文献1中记载的这些肽最初只限定于来自奶酪的水溶性组分的肽,所以关于其他序列的DPP-4抑制效果也尚不明确。另外,专利文献2选择2~8个氨基酸的长度、且包含Pro作为第一、第二、第三或第四N末端残基、或者从C末端残基或最后起第二位的C末端残基中包含Pro的肽作为优选的肽。上述文献着眼于DPP-4对从N末端起第2位具有Pro或Ala的生理活性肽特异性地发挥作用的方面。但是,对于实施例中评价了DPP-4抑制效果的水解物,虽然评价了分子量分布与DPP-4抑制以及GLP-1分泌的关系,但使用的水解物的组成尚不明确。
专利文献3也评价了猪或鱼的胶原蛋白肽的DPP-4抑制率,但并不存在具体的关于肽序列的记载。而且,肠促胰岛素作为DPP-4的底物被迅速分解,所以血中半衰期非常短。因此,通过DPP-4抑制剂来确保血中的肠促胰岛素浓度时,要求其在血液中迅速发挥DPP-4抑制作用,要求DPP-4抑制剂的生物体吸收性优异。
另一方面,专利文献4的实施例中使用的肽是使用反相柱分离收集市售的胶原蛋白肽,并特定是DPP-4抑制活性优异的肽,并没有系统性地评价肽序列和DPP-4抑制活性。另外,最初原料的胶原蛋白是进行胶原酶处理形成的市售的明胶。在利用胶原酶进行的分解中,由于N末端为Gly的肽是主要成分,所以制备N末端为Gly以外的肽或C末端为Gly的肽,无法评价DPP-4抑制活性。
另一方面,如非专利文献1~非专利文献3所示,DPP-4抑制剂对免疫系统发挥作用,还可用于皮肤疾病的治疗等医疗用途,因此其用途有可能扩大。
在这样的状况下,希望开发来自安全性高的肽的DPP-4抑制剂。
解决课题的方法
本发明人为了解决上述课题,参照胶原蛋白的氨基酸一级结构合成了各种肽,评价DPP-4抑制剂。结果发现:即使从N末端起第2位的氨基酸残基是Hyp,也能够发挥DPP-4抑制活性;即使从N末端起第2位是Pro或Ala,也存在不具有DPP-4抑制活性的肽;以及从N末端起第3位的氨基酸残基是Gly时,DPP-4抑制活性优异等,完成了本发明。而且,本发明中使用的肽是包含2~6个氨基酸的特定序列的肽,所以血中的转移性优异,可以迅速发挥DPP-4抑制作用,并且由于是来自胶原蛋白的氨基酸序列,所以安全性优异。
即,本发明提供DPP-4抑制剂,该DPP-4抑制剂以式(1):Xe-Pro/Ala/Hyp-Xa-Xb-Xc-Xd(式中,Xe表示等电点为5.9~6.3的氨基酸残基,Pro/Ala/Hyp表示Pro、Ala或Hyp,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly、Pro或缺失,Xc表示Pro、Ala或缺失,Xd表示氨基酸残基或缺失。)所示的肽作为有效成分。
另外,本发明还提供上述DPP-4抑制剂,其中,所述肽为下述式(A)或式(B)中的任意一种:
式(A):Gly-Pro/Ala-Xa-Xb-Xc-Xd(式中,Pro/Ala表示Pro或Ala,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失。)
式(B):Leu/Ile/Ala-Hyp/Pro-Xa-Xb-Xc(式中,Leu/Ile/Ala表示Leu、Ile或Ala,Hyp/Pro表示Hyp或Pro,Xa表示Hyp、Pro、Ile和Arg以外的氨基酸残基或缺失,Xb表示Pro或缺失,Xc表示Ala或缺失。)
另外,本发明还提供上述DPP-4抑制剂,其中,所述肽为下述式(A-1)、式(A-2)、式(B-1)或式(B-2)中的任意一种:
式(A-1):Gly-Pro-Xa-Xb-Xc-Xd(式中,Xa表示Hyp以及Val以外的等电点为3.0~6.2的氨基酸残基,Xb表示Gly,Xc表示Pro或缺失,Xd表示Ala以外的氨基酸残基或缺失。)、
式(A-2):Gly-Ala-Xa-Xb-Xc-Xd(式中,Xa表示等电点为5.8~6.2的氨基酸残基或缺失,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失。)、
式(B-1):Leu-Pro-Xa-Xb-Xc(式中,Xa表示Gly,Xb表示Pro或缺失,Xc表示Ala或缺失。)、
式(B-2):Leu/Ile-Hyp-Xa-Xb-Xc(式中,Leu/Ile表示Leu或Ile,Xa表示Gly,Xb表示Pro或缺失,Xc表示Ala或缺失。)。
除此之外,本发明还提供上述DPP-4抑制剂,其中,所述肽为选自Leu-Pro-Gly、Leu-Pro-Gly-Pro-Ala、Ile-Hyp-Gly、Leu-Hyp-Gly-Pro-Ala、Gly-Pro-Ala-Gly、Gly-Pro-Ala-Gly-Pro、Gly-Pro-Ala-Gly-Pro-Arg、Gly-Pro-Ala-Gly-Pro-Hyp、Gly-Pro-Ala-Gly-Pro-Ile、Gly-Pro-Leu-Gly-Pro-Val、Gly-Pro-Ile-Gly-Pro-Val、Gly-Ala-Ile-Gly-Pro-Ala、Gly-Ala-Ile-Gly-Pro-Ser、Gly-Ala-Val-Gly-Pro-Ala、Gly-Ala-Val-Gly-Pro、和Gly-Ala的任意一种以上。
而且,本发明还提供上述DPP-4抑制剂,其中,所述肽为式A-1、式A-2所示的任意一种以上和式B-1、式B-2所示的任意一种以上的混合物:
式A-1:Gly-Pro-Xa-Xb-Xc-Xd,式中,Xa表示Hyp以及Val以外的等电点为3.0~6.2的氨基酸残基,Xb表示Gly,Xc表示Pro或缺失,Xd表示Ala以外的氨基酸残基或缺失、
式A-2:Gly-Ala-Xa-Xb-Xc-Xd,式中,Xa表示等电点为5.8~6.2的氨基酸残基或缺失,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失、
式B-1:Leu-Pro-Xa-Xb-Xc,式中,Xa表示Gly,Xb表示Pro或缺失,Xc表示Ala或缺失、
式B-2:Leu/Ile-Hyp-Xa-Xb-Xc,式中,Leu/Ile表示Leu或Ile,Xa表示Gly,Xb表示Pro或缺失,Xc表示Ala或缺失。
发明效果
根据本发明,提供安全性优异、并且DPP-4抑制活性也优异的新的DPP-4抑制剂。
附图说明
图1是显示实施例6中合成的肽(Gly-Pro-Ile-Gly-Pro-Val)的DPP-4抑制曲线的图。
图2是显示实施例17中合成的肽(Leu-Pro-Gly)的DPP-4抑制曲线的图。
图3是显示氨基酸的等电点的一览表。
具体实施方式
第一本发明涉及DPP-4抑制剂,该DPP-4抑制剂以式(1):Xe-Pro/Ala/Hyp-Xa-Xb-Xc-Xd(式中,Xe表示等电点为5.9~6.3的氨基酸残基,Pro/Ala/Hyp表示Pro、Ala或Hyp,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly、Pro或缺失,Xc表示Pro、Ala或缺失,Xd表示氨基酸残基或缺失。)所示的肽作为有效成分。
人的DPP-4是由766个氨基酸构成的110kDa的膜蛋白,是在氨基侧末端配置有β螺旋结构域、在羧基侧末端配置有α/β水解酶结构域、且所述α/β水解酶结构域中存在3个催化残基(Ser630、His740、Asp708)的酶。在血中,胞外区和膜结合区被切断,以可溶型的形式存在。鉴于使二肽从自N末端起第2位具有Pro或Ala的肽中游离出来的特异性,例如如上述专利文献1所示,从氨基末端起第2位配有Ala或Pro的各种肽作为DPP-4抑制剂被提案,测定其IC50。另外,已知抑二肽素A(Ile-Pro-Ile)虽然是DPP-4的底物,但kcat和Km值均低,所以像抑制剂那样发挥作用,在专利文献1的实施例中,也同时记载着各种肽和抑二肽素A的IC50的测定值。
在这样的状况下,为了开发安全性优异、并且DPP-4抑制效果也优异的肽,作为含有大量的Pro的肽,参照胶原蛋白的氨基酸序列合成了各种肽。
需要说明的是,胶原蛋白是以3条多肽链的三重螺旋结构作为基本单元,是构成生物体的真皮、韧带、肌腱、骨、软骨等的蛋白。多个胶原蛋白分子缔合形成胶原蛋白纤维。构成胶原蛋白分子的氨基酸用-Gly-氨基酸X-氨基酸Y-表示,每3个Gly残基重复,具有所谓的被称作“胶原蛋白样序列”的一级结构。作为胶原蛋白所特有的氨基酸,有在Pro或Lys上加成有1个羟基的羟基脯氨酸(Hyp)或羟基赖氨酸(Hyl)等,在所述胶原蛋白样序列中,存在具有Pro作为所述氨基酸X的序列、或作为氨基酸Y存在许多Hyp,通过该胶原蛋白样序列维持着三重螺旋结构。在加工强韧的胶原蛋白时,利用酸或碱、酶进行水解,加工成明胶等。作为这样的酶,有胶原酶并经常使用,胶原酶主要是产生N末端为Gly的肽的肽链内切酶,因此,现有的胶原蛋白分解物中,N末端为Gly的肽是主要成分。因此,本发明并不限于这样的酶分解,为了研制DPP-4抑制活性优异的肽,参照胶原蛋白的氨基酸序列选出一部分序列、或者改变所选出的一部分序列以合成各种肽,评价对DPP-4的抑制率。
本发明中评价的肽是参照胶原蛋白的氨基酸序列的肽,所以在生物体内按照摄取胶原蛋白时的常规工序进行代谢,安全性高。作为参考,将来自牛的I型胶原蛋白α1链的序列记载在SEQ ID NO:14中。该序列作为NCBI的检索号NP 001029211来注册。需要说明的是,胶原蛋白中所含的Hyp是在胶原蛋白生成后用脯氨酸羟化酶修饰Pro而得到的产物。SEQ IDNO:14是翻译后修饰前的氨基酸序列,不包括Hyp。以下,对本发明进行详细说明。
本发明的DPP-4抑制剂以式(1):Xe-Pro/Ala/Hyp-Xa-Xb-Xc-Xd(式中,Xe表示等电点为5.9~6.3的氨基酸残基,Pro/Ala/Hyp表示Pro、Ala或Hyp,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly、Pro或缺失,Xc表示Pro、Ala或缺失,Xd表示氨基酸残基或缺失。)所示的肽作为有效成分。研究氨基酸序列和DPP-4抑制活性时明确了:当从N末端起第3位的氨基酸残基为Hyp或Pro时,不管其他氨基酸残基如何,DPP-4抑制活性均低或者不具有DPP-4抑制活性。另外,从N末端起第2位的氨基酸残基为Pro、Ala或Hyp时,DPP-4抑制活性优异,当满足上述条件时,N末端的氨基酸残基可以在等电点为5.9~6.3的范围内广泛选择。作为Xe,优选Gly、Ala、Ile、Leu、Pro,更优选为Gly、Ala、Ile或Leu。
作为上述式(1)所示的肽,可以是式(A):Gly-Pro/Ala-Xa-Xb-Xc-Xd(式中,Pro/Ala表示Pro或Ala,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失。)。
N末端为Gly时,Xa优选为Hyp、Pro和Arg以外的氨基酸残基。DPP-4具有使二肽从自N末端起第2位具有Pro或Ala的肽中游离出来的特异性,所以推测:从N末端第2位的氨基酸残基为Pro或Ala的肽具有DPP-4抑制活性。但是明确了:即使第2位的氨基酸残基为Pro或Ala,但若从N末端起第3位的氨基酸残基为Hyp或Pro,则DPP-4抑制活性极低、或者完全不存在。
而且,从N末端起第2位的氨基酸残基为Pro时,作为Xa,优选Ala、Gln、Glu、Ile、Leu、Val等的等电点为pH3.0~6.2的Hyp以外的氨基酸残基。特别优选为Ala、Gln、Glu、Ile、Leu、Val。
另一方面,从N末端起第2位的氨基酸残基为Ala时,作为Xa,有Val、Leu或Ile等的等电点为pH5.8~6.2的氨基酸残基或缺失。如后述的实施例所示,这与从N末端起第4位以后的氨基酸序列无关,是DPP-4抑制活性优异的缘故。需要说明的是,在本发明中,氨基酸的等电点依据图3所示的数值。
在上述式(A)中,Xb表示Gly或缺失,当Xb缺失时,形成三肽。
Xc表示Pro或缺失,Xc缺失时,形成四肽。另外,Xd可以是任一种氨基酸残基,或者可以缺失。本发明中使用的上述通式(A)所示的肽从N末端起具有Gly-Pro/Ala-的序列,如后述的实施例所示,在2~6个氨基酸的范围内,随着肽链的变长,DPP-4抑制活性有上升的趋势,但若超过5个氨基酸残基,则活性上升率不变。这意味着:DPP-4抑制活性由N末端起第4位的序列决定,与从N末端起第6位氨基酸残基的种类无关。结合作为Xd的各种氨基酸残基来评价DPP-4抑制活性时,在结合亲水性且等电点超过pH10的Arg、作为亚氨基酸的一种的Hyp、疎水性且等电点在弱酸性侧的Ile、Val、Ser、Ala等范围宽的氨基酸残基的肽中,发挥DPP-4抑制活性。
作为本发明中使用的式(A)所示的肽,可以是式(A-1):Gly-Pro-Xa-Xb-Xc-Xd(式中,Xa表示Hyp以外的等电点为3.0~6.2的氨基酸残基,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失。)。
作为上述式(A-1)所示的Xa,优选Ala、Gln、Glu、Ile、Val或Leu,作为Xd,优选Ala、Hyp、Leu、Val、Arg或缺失。
另外,作为本发明中使用的式(A)所示的肽,可以是式(A-2):Gly-Ala-Xa-Xb-Xc-Xd(式中,Xa表示等电点为5.8~6.2的氨基酸残基或缺失,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失。)。
作为上述式(A-2)所示的Xa,优选Leu、Ile、Val或缺失,作为Xd,优选Ala、Ser或缺失。
本发明的DPP-4抑制剂中,作为上述式(A)所示的肽,有Gly-Pro-Ala-Gly、Gly-Pro-Ala-Gly-Pro、Gly-Pro-Ala-Gly-Pro-Arg、Gly-Pro-Ala-Gly-Pro-Hyp、Gly-Pro-Ala-Gly-Pro-Ile、Gly-Pro-Leu-Gly-Pro-Val、Gly-Pro-Ile-Gly-Pro-Val、Gly-Pro-Val、Gly-Pro-Gln、Gly-Pro-Glu、Gly-Ala、Gly-Ala-Ile-Gly-Pro-Ala、Gly-Ala-Ile-Gly-Pro-Ser、Gly-Ala-Val-Gly-Pro-Ala、Gly-Ala-Val-Gly-Pro。
另外,本发明的DPP-4抑制剂可以是式(B):Leu/Ile/Ala-Hyp/Pro-Xa-Xb-Xc(式中,Leu/Ile/Ala表示Leu、Ile或Ala,Hyp/Pro表示Hyp或Pro,Xa表示Hyp、Pro、Ile和Arg以外的氨基酸残基或缺失,Xb表示Pro或缺失,Xc表示Ala或缺失。)所示的肽。
胶原蛋白中包含-Gly-氨基酸X-氨基酸Y-所示的胶原蛋白样序列,但在N末端不限于Gly的情况下评价DPP-4抑制活性时,明确了当从N末端起第3位的氨基酸残基为Gly时DPP-4抑制活性优异。此时,N末端的氨基酸残基为Leu、Ile或Ala,随着肽链变长,DPP-4抑制活性有增加的趋势。从N末端起第2位的氨基酸可以是Pro也可以是Hyp。DPP-4具有使二肽从自N末端起第2位具有Pro或Ala的肽中游离出来的特异性,但在N末端为Phe、Pro或Ala时,即使从N末端起第2位的氨基酸为Pro或Hyp,DPP-4抑制活性也低或完全不存在。这意味着:DPP-4抑制活性还受到N末端的氨基酸残基种类的影响。但是,即使在这种情况下,若结合Gly作为从N末端起第3位的氨基酸残基,则DPP-4抑制活性提高。Xa缺失时形成二肽,Xb缺失时形成三肽。需要说明的是,若参照胶原蛋白的氨基酸序列,则在式(B)中无法假设Xa的氨基酸残基为Ile,Xa为Hyp、Pro、Ile和Arg以外的氨基酸残基或缺失。
作为本发明中使用的式(B)所示的肽,可以优选使用式(B-1):Leu-Pro-Xa-Xb-Xc(式中,Xa表示Gly或缺失,Xb表示Pro或缺失,Xc表示Ala或缺失。)。
另外,作为本发明中使用的式(B)所示的肽,可以是式(B-2):Leu/Ile-Hyp-Xa-Xb-Xc(式中,Leu/Ile表示Leu或Ile,Xa表示Gly或缺失,Xb表示Pro或缺失,Xc表示Ala或缺失。)。
而且,作为本发明中使用的式(B)所示的肽,可以是式(B-3):Ala-Hyp/Pro-Gly(式中,Hyp/Pro表示Hyp或Pro。)。
本发明的DPP-4抑制剂中,作为上述式(B)所示的肽,有Leu-Pro、Leu-Pro-Gly、Leu-Pro-Gly-Pro-Ala、Ala-Pro-Gly、Ile-Hyp-Gly和Leu-Hyp-Gly-Pro-Ala。
本发明的DPP-4抑制剂中使用的上述肽可以是构成医学上可接受的盐的肽。需要说明的是,医学上可接受的盐是指,药理学上可接受且对给药的受试者基本无毒的作为本发明化合物的盐的形式。作为上述肽的药学上可接受的盐,有钠盐、钙盐、镁盐、钙盐等无机盐;乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、羟基丁酸盐、苹果酸盐、马来酸盐、丙二酸盐、琥珀酸盐、己二酸酸、酒石酸、枸橼酸盐、戊二酸盐等有机酸盐;盐酸盐、磷酸盐、盐酸盐、硫酸盐、羧酸盐、膦酸盐、磺酸盐等加成盐。
如上所述,本发明的DPP-4抑制剂是参照胶原蛋白的氨基酸一级序列来选择DPP-4抑制效果优异的抑制剂、或者改变一部分序列而得到的抑制剂,可以通过肽合成来制备。但是,也可以是通过其他方法制备的抑制剂。
本发明的DPP-4抑制剂,通过口服给药,可以在生物体内通过抑制DPP-4来降低血糖值,可以用作糖尿病的预防药、治疗药。口服给药时,作为本发明的DPP-4抑制剂的剂型,除了直接使用肽以外,还可以混合其他的赋形剂以制成片剂、细粒剂、丸剂、锭剂等,也可以装在胶囊中制成胶囊剂,更可以制成液体制剂等。口服给药时,考虑到治疗或预防的目的、症状、体重、年龄等条件,可以适当选择。另外,还可以作为补充物来摄取。
关于本发明的DPP-4抑制剂的给药量,可以根据给药形式、给药目的、受试者的年龄等适当选择。通常,口服给药时,成人每天0.001~100mg/kg,优选0.01~50mg/kg,更优选为0.1~20mg/kg。当为注射剂时,成人每天例如0.0001~50mg/kg,优选0.001~20mg/kg,特别优选为0.01~10mg/kg。
作为这样的肽,可以优选使用式(A):Gly-Pro/Ala-Xa-Xb-Xc-Xd(式中,Pro/Ala表示Pro或Ala,Xa表示Hyp、Pro和Arg以外的氨基酸残基或缺失,Xb表示Gly或缺失,Xc表示Pro或缺失,Xd表示氨基酸残基或缺失。)所示的任意一种以上和式(B):Leu/Ile/Ala-Hyp/Pro-Xa-Xb-Xc(式中,Leu/Ile/Ala表示Leu、Ile或Ala,Hyp/Pro表示Hyp或Pro,Xa表示Hyp、Pro、Ile和Arg以外的氨基酸残基或缺失,Xb表示Pro或缺失,Xc表示Ala或缺失。)所示的任意一种以上的混合物作为DPP-4抑制剂。这是由于:虽然均来自胶原蛋白的氨基酸序列,但式(A)的N末端为Gly,而式(B)的N末端为Gly以外的氨基酸残基,所以摄取后的代谢速度等不同,可以期待并用效果的缘故。
本发明的DPP-4抑制剂,可以将其混合在食品中经口摄取。作为这样的混合有本发明的DPP-4抑制剂的食品,有包含野菜或果实、乳酸菌等的果汁等饮料、果冻、酸奶、布丁、冰激凌等半流动性食品等,此外还可以混合在其他食材中制成固体食品。
另外,还指出DPP-4抑制剂具有T淋巴细胞的增殖效果,其缓和自身免疫性脊椎炎、多发性硬化症、关节炎、风湿病等自身免疫疾病。因此,本发明的DPP-4抑制剂也有可能能够用于上述疾病。此时的用途并不限于内服,还可以是注射到炎症部位等的外科处方。
实施例
接下来,例举实施例以具体说明本发明,但这些实施例对本发明没有任何限制。
DPP-4抑制活性的测定方法
(1)DPP-4抑制率的测定方法
将1mg试样溶解在1ml 50mM的Tris-盐酸缓冲液(pH7.5)中,将所得的35μl样品液和15μl溶解在50mM的Tris-盐酸缓冲液(pH7.5)中的DPP-4(シグマ公司制、来自猪肾脏;8.6mU/ml)在微板孔(NUNC公司制、商品名“237015”)中混合,在37℃下培养10分钟。
向其中添加50μl预先保温在37℃的底物溶液(将甘氨酰Pro-4-甲基香豆素-7-酰胺(Gly-Pro-MCA)溶解在50mM的Tris-盐酸缓冲液(pH7.5)中使浓度达到10μM的溶液)并进行混合,在37℃下反应20分钟。
使用酶标仪型荧光检测器(コロナ电器公司制、商品名“SH-9000”),随时间测定通过DPP-4而游离的7-氨基-4-甲基香豆素(AMC)的荧光强度。需要说明的是,在激发波长380nm、测定波长460nm下进行测定。需要说明的是,使用等量的50mM的Tris-盐酸缓冲液(pH7.5)代替样品来作为对照,测定其荧光强度。
DPP-4的活性用反应时间中的荧光强度变化量的平均梯度表示,关于DPP-4抑制率,以对照为100%,从所述对照中减去样品的活性而得到的值作为抑制率(%)而算出。
(2)IC50值的测定方法
根据上述的DPP-4抑制率的测定方法,使样品浓度在0.001~7.2μmol/ml之间变化,得到抑制率,算出DPP-4活性的50%抑制浓度(IC50值)。
(实施例1)
利用使用了アプライドバイオシステムズ公司制的肽自动合成装置(433A)的Fmoc固相合成法,合成表1所示的Gly-Pro-Ala-Gly-Pro。
进行合成时,将位于寡肽的C-末端的氨基酸担载在树脂上,利用使N-末端的每一个氨基酸伸长的逐步延伸法进行合成,伸长反应中的肽耦合反应使用二异丙基碳化二亚胺(DIC)和1-羟基苯并三唑(HOBt)作为缩合剂。需要说明的是,伸长的N-末端氨基酸的氨基用9-芴基甲氧基羰基(Fmoc)保护起来,但由于寡肽的构成氨基酸中不包含具有反应活性的侧链,所以特别是没有对侧链进行保护。
首先,将用Fmoc保护位于寡肽C-末端的Pro的N-末端、并将C-末端担载在树脂上而得到的0.5g Fmoc-Pro-Wang树脂(0.5-0.8mmol/g、Bachem公司制)担载在树脂上。将其装入肽自动合成装置的反应容器中,使用20%哌啶-DMF溶液进行10分钟的Fmoc的脱保护。用DMF清洗树脂1分钟,之后在反应溶液中分别加入1mmol的Fmoc-Gly-OH、DIC和HOBt。反应1小时后,确认没有检测到未反应的N-末端,用DMF清洗1分钟。再用20%哌啶-DMF进行Fmoc的脱保护,用DMF清洗树脂后,分别加入1mmol的Fmoc-Ala-OH、DIC和HOBt进行反应。以下,按照相同的方法,对Pro、Gly也进行上述操作,使每一个氨基酸伸长。得到的Fmoc-Gly-Pro-Ala-Gly-Pro-Wang树脂用20%哌啶-DMF溶液进行10分钟的脱保护,之后减压干燥。得到的干燥树脂用TFA(10mL×3次)进行处理,将寡肽粗产物从树脂中洗脱到TFA中。
在室温下减压馏去所得的TFA溶液,之后在冰冷下向残余物中加入10mL二乙醚,得到沉淀物。沉淀物进一步用二乙醚(10mL×5次)清洗,将沉淀物减压干燥。此时得到的粗产物的重量为38.5mg(收率为29.8%)。将得到的粗产物溶解在纯净水中,利用反相高效液相色谱法(HPLC)进行分离收集,进行纯化。得到的纯化物通过薄层色谱法(TLC)、HPLC确认纯度后,通过Edman法确定氨基酸序列,再使用质量分析装置(MALDI-TOF)确认是目标分子量。
最终的目的物的重量为30.7mg,收率为23.8%。
使用所得的肽测定DPP-4抑制率和IC50值。结果见表1。
(实施例2~实施例9)
使用Fmoc-Arg(Pbf)-Wang树脂、Fmoc-Hyp-Wang树脂、Fmoc-Ile-Wang树脂、Fmoc-Val-Wang树脂、Fmoc-Gln-Wang、Fmoc-Pro-Wang树脂作为寡肽的C-末端氨基酸,使用Fmoc-Gly-OH、Fmoc-Pro-OH、Fmoc-Leu-OH、Fmoc-Ile-OH作为Fmoc基保护氨基酸,根据实施例1来合成表1所示的Gly-Pro-Ala-Gly-Pro-Arg(实施例2)、Gly-Pro-Ala-Gly-Pro-Hyp(实施例3)、Gly-Pro-Ala-Gly-Pro-Ile(实施例4)、Gly-Pro-Leu-Gly-Pro-Val(实施例5)、Gly-Pro-Ile-Gly-Pro-Val(实施例6)、Gly-Pro-Val(实施例7)、Gly-Pro-Gln(实施例8)、Gly-Pro-Ala-Gly(实施例9)。
需要说明的是,实施例2的肽合成不同于实施例1,由于使用包含2个氨基的Arg,所以使用Arg侧链的胍基已用Pbf基(2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基)保护起来的Fmoc-Arg(Pbf)-Wang树脂,最后通过TFA除去Pbf基。
同样,在实施例8的肽合成中,由于使用侧链包含酰胺基的Gln,所以使用Gln侧链的酰胺基已用Trt基(三苯甲基)保护起来的Fmoc-Gln(Trt)-Wang树脂,最后通过TFA除去Trt基。
使用得到的肽,与实施例1同样操作,测定DPP-4抑制率。结果见表1。另外,制作实施例6中合成的肽(Gly-Pro-Ile-Gly-Pro-Val)的DPP-4抑制曲线。该抑制曲线见图1。
(实施例10~实施例15)
使用氨基已用Fmoc基保护起来的氨基酸,依照实施例1合成表1所示的实施例10~15的肽,制作DPP-4抑制曲线。结果见表1。需要说明的是,实施例10的肽合成与实施例1不同,由于使用包含2个羧基的Glu,所以使用Glu侧链的羧基已用叔丁基(But基)保护起来的Fmoc-Glu(OBut)-Wang树脂,最后通过TFA除去But基。
另外,关于实施例13的肽,使用Fmoc-Ser(But)-Wang树脂作为寡肽的C-末端氨基酸,依照实施例1合成Gly-Ala-Ile-Gly-Pro-Ser。需要说明的是,与实施例1不同,由于使用包含羟基的丝氨酸,所以使用Ser侧链的羟基已用叔丁基(But基)保护起来的Fmoc-Ser(But)-Wang树脂,最后通过TFA除去But基。
(比较例1~比较例3)
使用氨基已用Fmoc基保护起来的氨基酸,依照实施例1合成表1所示的比较例1~比较例3的肽。使用得到的肽,测定DPP-4抑制率和IC50值。结果见表1。需要说明的是,比较例1~比较例3的肽均为构成SEQ ID NO:14的一部分氨基酸序列的肽。
需要说明的是,在本申请中,以满足根据上述测定方法测定的DPP-4抑制率为30%以下、或IC50为10μmol/ml以上的任一种肽作为比较例。
[表1]
(结果)
如表1的实施例1~6、9、12~15所示,当N末端为Gly、且从N末端起第2位的氨基酸残基为Pro或Ala的4~6氨基酸的肽的N末端的第4位氨基酸残基为Gly时,不论从N末端起第3位的氨基酸的种类如何,DPP-4抑制活性均优异。特别是,如实施例1~4和实施例9所示,具有Gly-Pro-Ala-Gly的序列的肽,随着肽链的变长,其DPP-4抑制活性增加。
比较表1的比较例1~比较例3和实施例7、8、10以及11可知:当为二肽或三肽时,即使从N末端起第2位是Pro或Ala,但若第3位是Hyp,则DPP-4抑制活性也极低或者不存在DPP-4抑制活性。
(实施例16~实施例25)
使用氨基已用Fmoc基保护起来的氨基酸,依照实施例1合成表2所示的肽。另外,制作实施例17中合成的肽(Leu-Pro-Gly)的DPP-4抑制曲线。该抑制曲线见图2。
(比较例4~比较例7)
使用氨基已用Fmoc基保护起来的氨基酸,依照实施例1合成表2所示的比较例4~比较例7的肽。使用得到的肽,测定DPP-4抑制率和IC50值。结果见表2。需要说明的是,比较例4~比较例7的肽均为构成SEQ ID NO:14的一部分氨基酸序列的肽。
[表2]
(结果)
由表2的实施例16~实施例25可知:即使从N末端起第2位的氨基酸残基是Hyp,也可发挥DPP-4抑制活性。另一方面,比较实施例20和比较例4~7可知:从N末端起第2位的氨基酸残基为Pro或Hyp的二肽,根据N末端的氨基酸残基的种类,而具有DPP-4抑制活性大不相同的倾向,当为Phe、Pro时,完全不存在DPP-4抑制活性。
比较实施例25和比较例6时,若在Ala-Hyp的二肽上结合Gly作为从N末端起第3位的氨基酸残基,则可发挥DPP-4抑制活性。如实施例21~实施例25所示,并不限于N末端的氨基酸残基,均可观察到该倾向。而且,如实施例16~实施例18所示,从N末端起第2位的氨基酸残基为Pro时,也可观察到下述倾向:若在第3位结合Gly,则DPP-4抑制活性增加,若肽链变长,则DPP-4抑制活性进一步增强。
本发明基于2011年11月4日申请的日本国专利申请2011-242050号。日本国专利申请2011-242050号的说明书、专利申请的范围、附图全体均作为参照而纳入本说明书中。
产业实用性
根据本发明,可以制备来自胶原蛋白的安全性优异的DPP-4抑制剂,本发明是有用的。
序列表
<110> Nippi, Incorporated
<120> DPP-4 抑制剂
<130> 12F072-PCT
<150> 2011-242050
<151> 2011-11-04
<160> 14
<170> PatentIn version 3.5
<210> 1
<211> 4
<212> PRT
<213> 牛(Bos taurus)
<400> 1
Gly Pro Ala Gly
1
<210> 2
<211> 5
<212> PRT
<213> 牛(Bos taurus)
<400> 2
Gly Pro Ala Gly Pro
1 5
<210> 3
<211> 6
<212> PRT
<213> 牛(Bos taurus)
<400> 3
Gly Pro Ala Gly Pro Arg
1 5
<210> 4
<211> 6
<212> PRT
<213> 牛(Bos taurus)
<220>
<221> MOD_RES
<222> (6)..(6)
<223> 羟基化。Xaa代表3Hyp或者4Hyp。
<400> 4
Gly Pro Ala Gly Pro Xaa
1 5
<210> 5
<211> 6
<212> PRT
<213> 牛(Bos taurus)
<400> 5
Gly Pro Ala Gly Pro Ile
1 5
<210> 6
<211> 6
<212> PRT
<213> 人工序列
<220>
<223> 经修饰的牛胶原蛋白肽
<220>
<221> 突变
<222> (3)..(3)
<223> 由Ile修饰而来
<400> 6
Gly Pro Leu Gly Pro Val
1 5
<210> 7
<211> 6
<212> PRT
<213> 牛(Bos taurus)
<400> 7
Gly Pro Ile Gly Pro Val
1 5
<210> 8
<211> 6
<212> PRT
<213> 人工序列
<220>
<221> 突变
<222> (3)..(3)
<223> 由Ser修饰而来
<400> 8
Gly Ala Ile Gly Pro Ala
1 5
<210> 9
<211> 6
<212> PRT
<213> 牛(Bos taurus)
<400> 9
Gly Ala Ile Gly Pro Ser
1 5
<210> 10
<211> 6
<212> PRT
<213> 牛(Bos taurus)
<400> 10
Gly Ala Val Gly Pro Ala
1 5
<210> 11
<211> 5
<212> PRT
<213> 牛(Bos taurus)
Gly Ala Val Gly Pro
1 5
<210> 12
<211> 5
<212> PRT
<213> 牛(Bos taurus)
<400> 12
Leu Pro Gly Pro Ala
1 5
<210> 13
<211> 5
<212> PRT
<213> 牛(Bos taurus)
<220>
<221> MOD_RES
<222> (2)..(2)
<223> 羟基化。Xaa代表3Hyp或4Hyp。
<400> 13
Leu Xaa Gly Pro Ala
1 5
<210> 14
<211> 1463
<212> PRT
<213> 牛(Bos taurus)
<400> 14
Met Phe Ser Phe Val Asp Leu Arg Leu Leu Leu Leu Leu Ala Ala Thr
1 5 10 15
Ala Leu Leu Thr His Gly Gln Glu Glu Gly Gln Glu Glu Gly Gln Glu
20 25 30
Glu Asp Ile Pro Pro Val Thr Cys Val Gln Asn Gly Leu Arg Tyr His
35 40 45
Asp Arg Asp Val Trp Lys Pro Val Pro Cys Gln Ile Cys Val Cys Asp
50 55 60
Asn Gly Asn Val Leu Cys Asp Asp Val Ile Cys Asp Glu Leu Lys Asp
65 70 75 80
Cys Pro Asn Ala Lys Val Pro Thr Asp Glu Cys Cys Pro Val Cys Pro
85 90 95
Glu Gly Gln Glu Ser Pro Thr Asp Gln Glu Thr Thr Gly Val Glu Gly
100 105 110
Pro Lys Gly Asp Thr Gly Pro Arg Gly Pro Arg Gly Pro Ala Gly Pro
115 120 125
Pro Gly Arg Asp Gly Ile Pro Gly Gln Pro Gly Leu Pro Gly Pro Pro
130 135 140
Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Leu Gly Gly Asn Phe Ala
145 150 155 160
Pro Gln Leu Ser Tyr Gly Tyr Asp Glu Lys Ser Thr Gly Ile Ser Val
165 170 175
Pro Gly Pro Met Gly Pro Ser Gly Pro Arg Gly Leu Pro Gly Pro Pro
180 185 190
Gly Ala Pro Gly Pro Gln Gly Phe Gln Gly Pro Pro Gly Glu Pro Gly
195 200 205
Glu Pro Gly Ala Ser Gly Pro Met Gly Pro Arg Gly Pro Pro Gly Pro
210 215 220
Pro Gly Lys Asn Gly Asp Asp Gly Glu Ala Gly Lys Pro Gly Arg Pro
225 230 235 240
Gly Glu Arg Gly Pro Pro Gly Pro Gln Gly Ala Arg Gly Leu Pro Gly
245 250 255
Thr Ala Gly Leu Pro Gly Met Lys Gly His Arg Gly Phe Ser Gly Leu
260 265 270
Asp Gly Ala Lys Gly Asp Ala Gly Pro Ala Gly Pro Lys Gly Glu Pro
275 280 285
Gly Ser Pro Gly Glu Asn Gly Ala Pro Gly Gln Met Gly Pro Arg Gly
290 295 300
Leu Pro Gly Glu Arg Gly Arg Pro Gly Ala Pro Gly Pro Ala Gly Ala
305 310 315 320
Arg Gly Asn Asp Gly Ala Thr Gly Ala Ala Gly Pro Pro Gly Pro Thr
325 330 335
Gly Pro Ala Gly Pro Pro Gly Phe Pro Gly Ala Val Gly Ala Lys Gly
340 345 350
Glu Gly Gly Pro Gln Gly Pro Arg Gly Ser Glu Gly Pro Gln Gly Val
355 360 365
Arg Gly Glu Pro Gly Pro Pro Gly Pro Ala Gly Ala Ala Gly Pro Ala
370 375 380
Gly Asn Pro Gly Ala Asp Gly Gln Pro Gly Ala Lys Gly Ala Asn Gly
385 390 395 400
Ala Pro Gly Ile Ala Gly Ala Pro Gly Phe Pro Gly Ala Arg Gly Pro
405 410 415
Ser Gly Pro Gln Gly Pro Ser Gly Pro Pro Gly Pro Lys Gly Asn Ser
420 425 430
Gly Glu Pro Gly Ala Pro Gly Ser Lys Gly Asp Thr Gly Ala Lys Gly
435 440 445
Glu Pro Gly Pro Thr Gly Ile Gln Gly Pro Pro Gly Pro Ala Gly Glu
450 455 460
Glu Gly Lys Arg Gly Ala Arg Gly Glu Pro Gly Pro Ala Gly Leu Pro
465 470 475 480
Gly Pro Pro Gly Glu Arg Gly Gly Pro Gly Ser Arg Gly Phe Pro Gly
485 490 495
Ala Asp Gly Val Ala Gly Pro Lys Gly Pro Ala Gly Glu Arg Gly Ala
500 505 510
Pro Gly Pro Ala Gly Pro Lys Gly Ser Pro Gly Glu Ala Gly Arg Pro
515 520 525
Gly Glu Ala Gly Leu Pro Gly Ala Lys Gly Leu Thr Gly Ser Pro Gly
530 535 540
Ser Pro Gly Pro Asp Gly Lys Thr Gly Pro Pro Gly Pro Ala Gly Gln
545 550 555 560
Asp Gly Arg Pro Gly Pro Pro Gly Pro Pro Gly Ala Arg Gly Gln Ala
565 570 575
Gly Val Met Gly Phe Pro Gly Pro Lys Gly Ala Ala Gly Glu Pro Gly
580 585 590
Lys Ala Gly Glu Arg Gly Val Pro Gly Pro Pro Gly Ala Val Gly Pro
595 600 605
Ala Gly Lys Asp Gly Glu Ala Gly Ala Gln Gly Pro Pro Gly Pro Ala
610 615 620
Gly Pro Ala Gly Glu Arg Gly Glu Gln Gly Pro Ala Gly Ser Pro Gly
625 630 635 640
Phe Gln Gly Leu Pro Gly Pro Ala Gly Pro Pro Gly Glu Ala Gly Lys
645 650 655
Pro Gly Glu Gln Gly Val Pro Gly Asp Leu Gly Ala Pro Gly Pro Ser
660 665 670
Gly Ala Arg Gly Glu Arg Gly Phe Pro Gly Glu Arg Gly Val Gln Gly
675 680 685
Pro Pro Gly Pro Ala Gly Pro Arg Gly Ala Asn Gly Ala Pro Gly Asn
690 695 700
Asp Gly Ala Lys Gly Asp Ala Gly Ala Pro Gly Ala Pro Gly Ser Gln
705 710 715 720
Gly Ala Pro Gly Leu Gln Gly Met Pro Gly Glu Arg Gly Ala Ala Gly
725 730 735
Leu Pro Gly Pro Lys Gly Asp Arg Gly Asp Ala Gly Pro Lys Gly Ala
740 745 750
Asp Gly Ala Pro Gly Lys Asp Gly Val Arg Gly Leu Thr Gly Pro Ile
755 760 765
Gly Pro Pro Gly Pro Ala Gly Ala Pro Gly Asp Lys Gly Glu Ala Gly
770 775 780
Pro Ser Gly Pro Ala Gly Pro Thr Gly Ala Arg Gly Ala Pro Gly Asp
785 790 795 800
Arg Gly Glu Pro Gly Pro Pro Gly Pro Ala Gly Phe Ala Gly Pro Pro
805 810 815
Gly Ala Asp Gly Gln Pro Gly Ala Lys Gly Glu Pro Gly Asp Ala Gly
820 825 830
Ala Lys Gly Asp Ala Gly Pro Pro Gly Pro Ala Gly Pro Ala Gly Pro
835 840 845
Pro Gly Pro Ile Gly Asn Val Gly Ala Pro Gly Pro Lys Gly Ala Arg
850 855 860
Gly Ser Ala Gly Pro Pro Gly Ala Thr Gly Phe Pro Gly Ala Ala Gly
865 870 875 880
Arg Val Gly Pro Pro Gly Pro Ser Gly Asn Ala Gly Pro Pro Gly Pro
885 890 895
Pro Gly Pro Ala Gly Lys Glu Gly Ser Lys Gly Pro Arg Gly Glu Thr
900 905 910
Gly Pro Ala Gly Arg Pro Gly Glu Val Gly Pro Pro Gly Pro Pro Gly
915 920 925
Pro Ala Gly Glu Lys Gly Ala Pro Gly Ala Asp Gly Pro Ala Gly Ala
930 935 940
Pro Gly Thr Pro Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val
945 950 955 960
Gly Leu Pro Gly Gln Arg Gly Glu Arg Gly Phe Pro Gly Leu Pro Gly
965 970 975
Pro Ser Gly Glu Pro Gly Lys Gln Gly Pro Ser Gly Ala Ser Gly Glu
980 985 990
Arg Gly Pro Pro Gly Pro Met Gly Pro Pro Gly Leu Ala Gly Pro Pro
995 1000 1005
Gly Glu Ser Gly Arg Glu Gly Ala Pro Gly Ala Glu Gly Ser Pro
1010 1015 1020
Gly Arg Asp Gly Ser Pro Gly Ala Lys Gly Asp Arg Gly Glu Thr
1025 1030 1035
Gly Pro Ala Gly Pro Pro Gly Ala Pro Gly Ala Pro Gly Ala Pro
1040 1045 1050
Gly Pro Val Gly Pro Ala Gly Lys Ser Gly Asp Arg Gly Glu Thr
1055 1060 1065
Gly Pro Ala Gly Pro Ala Gly Pro Ile Gly Pro Val Gly Ala Arg
1070 1075 1080
Gly Pro Ala Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly Glu Thr
1085 1090 1095
Gly Glu Gln Gly Asp Arg Gly Ile Lys Gly His Arg Gly Phe Ser
1100 1105 1110
Gly Leu Gln Gly Pro Pro Gly Pro Pro Gly Ser Pro Gly Glu Gln
1115 1120 1125
Gly Pro Ser Gly Ala Ser Gly Pro Ala Gly Pro Arg Gly Pro Pro
1130 1135 1140
Gly Ser Ala Gly Ser Pro Gly Lys Asp Gly Leu Asn Gly Leu Pro
1145 1150 1155
Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala
1160 1165 1170
Gly Pro Ala Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro
1175 1180 1185
Gly Pro Pro Ser Gly Gly Tyr Asp Leu Ser Phe Leu Pro Gln Pro
1190 1195 1200
Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asp
1205 1210 1215
Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr
1220 1225 1230
Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu
1235 1240 1245
Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met
1250 1255 1260
Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn
1265 1270 1275
Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu
1280 1285 1290
Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln
1295 1300 1305
Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Glu Lys Arg His Val
1310 1315 1320
Trp Tyr Gly Glu Ser Met Thr Gly Gly Phe Gln Phe Glu Tyr Gly
1325 1330 1335
Gly Gln Gly Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe
1340 1345 1350
Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His
1355 1360 1365
Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu
1370 1375 1380
Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg
1385 1390 1395
Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Tyr Asp Gly
1400 1405 1410
Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr
1415 1420 1425
Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro
1430 1435 1440
Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly
1445 1450 1455
Pro Ala Cys Phe Leu
1460
Claims (2)
1.一种DPP-4抑制剂,包含来自胶原蛋白的肽,其中,所述肽为Gly-Pro-Ala-Gly-Pro-Ile。
2.根据权利要求1所述的DPP-4抑制剂,其中,进一步包含选自由Leu-Pro-Gly、Leu-Pro-Gly-Pro-Ala、Ile-Hyp-Gly、Leu-Hyp-Gly-Pro-Ala、Gly-Pro-Ala-Gly、Gly-Ala-Ile-Gly-Pro-Ala、Gly-Ala-Ile-Gly-Pro-Ser、Gly-Ala-Val-Gly-Pro-Ala、Gly-Ala-Val-Gly-Pro和Gly-Ala组成的组中的一种以上的肽。
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JP2011-242050 | 2011-11-04 | ||
JP2011242050 | 2011-11-04 | ||
CN201280054376.XA CN103987724A (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
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CN201280054376.XA Division CN103987724A (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
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CN106866814B true CN106866814B (zh) | 2020-06-23 |
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CN201710090274.8A Active CN106831980B (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
CN201710090588.8A Active CN106866814B (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
CN201610681645.5A Active CN106243216B (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
CN201280054376.XA Pending CN103987724A (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
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CN201710090274.8A Active CN106831980B (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
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CN201610681645.5A Active CN106243216B (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
CN201280054376.XA Pending CN103987724A (zh) | 2011-11-04 | 2012-11-02 | Dpp-4抑制剂 |
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US (1) | US9340579B2 (zh) |
JP (1) | JP5926279B2 (zh) |
CN (4) | CN106831980B (zh) |
CA (1) | CA2854289C (zh) |
HK (1) | HK1200840A1 (zh) |
WO (1) | WO2013065832A1 (zh) |
Families Citing this family (14)
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WO2014017474A1 (ja) * | 2012-07-25 | 2014-01-30 | 株式会社ニッピ | コラーゲンペプチド組成物の製造方法、dpp-4阻害剤および血糖値上昇抑制剤 |
JP6369951B2 (ja) * | 2015-08-26 | 2018-08-08 | 三井農林株式会社 | ジペプチジルペプチダーゼ−iv阻害剤 |
ES2899961T3 (es) * | 2015-12-16 | 2022-03-15 | Dsm Ip Assets Bv | Inhibidores de DPP4 para uso médico y cosmético |
JP6517732B2 (ja) * | 2016-06-01 | 2019-05-22 | 株式会社ニッピ | Dpp−4阻害剤、血糖値上昇抑制剤およびdpp−4阻害用食品 |
ES2702617B2 (es) * | 2017-09-04 | 2019-11-18 | Univ Rovira I Virgili | Hidrolizados de garras de patas de pollo, sus péptidos y usos de los mismos |
US11180541B2 (en) | 2017-09-28 | 2021-11-23 | Geltor, Inc. | Recombinant collagen and elastin molecules and uses thereof |
CN108129552B (zh) * | 2017-12-22 | 2023-07-07 | 大连深蓝肽科技研发有限公司 | 一种海参来源的抗氧化活性肽及提取方法 |
TW202104254A (zh) | 2019-04-12 | 2021-02-01 | 美商格爾托公司 | 重組彈性蛋白及其生產 |
JP7545479B2 (ja) | 2019-12-27 | 2024-09-04 | サントリーホールディングス株式会社 | ペプチドを含む組成物、その製造方法、並びにペプチドの使用 |
CN113024636B (zh) * | 2021-02-09 | 2022-01-18 | 宁波绿之健药业有限公司 | 一种具有缓解高尿酸血症和调节肠道菌群的六肽及其应用 |
MX2023010902A (es) | 2021-03-18 | 2023-09-27 | Seagen Inc | Liberacion selectiva de farmacos a partir de conjugados internalizados de compuestos biologicamente activos. |
CN114349819B (zh) * | 2021-12-23 | 2023-09-29 | 华南理工大学 | 具有DPP-IV抑制活性的Gly-Pro-型肽及其应用 |
CN114349849B (zh) * | 2021-12-23 | 2023-08-04 | 华南理工大学 | 一种具有降血糖功效的胶原蛋白酶解物及其制备方法和应用 |
CN114349818A (zh) * | 2021-12-31 | 2022-04-15 | 华南理工大学 | 一类具有双靶点降糖功能的三肽及其应用 |
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2012
- 2012-11-02 CN CN201710090274.8A patent/CN106831980B/zh active Active
- 2012-11-02 CN CN201710090588.8A patent/CN106866814B/zh active Active
- 2012-11-02 CA CA2854289A patent/CA2854289C/en active Active
- 2012-11-02 JP JP2013541862A patent/JP5926279B2/ja active Active
- 2012-11-02 WO PCT/JP2012/078511 patent/WO2013065832A1/ja active Application Filing
- 2012-11-02 CN CN201610681645.5A patent/CN106243216B/zh active Active
- 2012-11-02 CN CN201280054376.XA patent/CN103987724A/zh active Pending
- 2012-11-02 US US14/356,023 patent/US9340579B2/en active Active
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JP2011201923A (ja) * | 2005-07-01 | 2011-10-13 | Snow Brand Milk Products Co Ltd | ジペプチジルペプチダーゼiv阻害剤 |
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Publication number | Publication date |
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CA2854289A1 (en) | 2013-05-10 |
CN103987724A (zh) | 2014-08-13 |
CN106831980A (zh) | 2017-06-13 |
CN106243216B (zh) | 2019-12-20 |
HK1200840A1 (zh) | 2015-08-14 |
US9340579B2 (en) | 2016-05-17 |
CN106831980B (zh) | 2020-09-15 |
CA2854289C (en) | 2019-11-12 |
US20140309401A1 (en) | 2014-10-16 |
JP5926279B2 (ja) | 2016-06-01 |
JPWO2013065832A1 (ja) | 2015-04-02 |
WO2013065832A1 (ja) | 2013-05-10 |
CN106243216A (zh) | 2016-12-21 |
CN106866814A (zh) | 2017-06-20 |
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