CN102224161A - 抗炎症肽 - Google Patents
抗炎症肽 Download PDFInfo
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- CN102224161A CN102224161A CN2008801320419A CN200880132041A CN102224161A CN 102224161 A CN102224161 A CN 102224161A CN 2008801320419 A CN2008801320419 A CN 2008801320419A CN 200880132041 A CN200880132041 A CN 200880132041A CN 102224161 A CN102224161 A CN 102224161A
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Abstract
本发明提供了抗炎症组合物，其具有高效力、不会造成相关的副作用、容易摄取，且因为它的低成本和高安全性，也可以长时间施用。本发明涉及包含由pyroGlu-(X)n-A表示的氨基酸序列的肽或其盐，其中X独立地是Gln、Asn或Pro；A表示Gln、Asn、Leu、Ile、Met、Val或Phe；且n表示0-2的整数，以及包含它们的抗炎症组合物。
Description
技术领域
本发明涉及具有抗炎症活性的肽和含有所述肽作为活性成分的抗炎症组合物。
背景技术
已知肿瘤坏死因子(TNF)、尤其是TNF-α是由炎症细胞释放的，并造成各种细胞毒性反应、免疫反应和炎症反应。已知TNF-α参与许多炎症和自身免疫病的发生和发展，并在释放进血液和作用于全身时，进一步造成严重的败血症和脓毒性休克。因为TNF-α是与活体的免疫系统广泛相关的因子，因此积极地进行抑制TNF-α的药剂的开发。TNF-α以无活性形式被生物合成，并通过蛋白酶的切割变成活性形式；负责该活化的酶被称作肿瘤坏死因子-转化酶 (TACE)。因而，抑制该TACE的物质可以治疗、改善或预防归因于TNF-α的疾病、病理学状况、异常状况、疼痛、不利征状等。
白介素-1 (IL-1)是刺激前列腺素、胶原酶和磷脂酶的生产、嗜碱性粒细胞和嗜酸性粒细胞的去粒、和嗜中性粒细胞的活化的主要炎症细胞因子。IL-1具有非常广范围的生理效应。它通过活化或促进免疫细胞的分化/增殖，引起局部的或全身的炎症反应，并参与发烧、急性期蛋白的诱导、破骨细胞的活化等。因为IL-1是与活体的免疫系统广泛相关的因子，因此积极地进行抑制IL-1的药剂的开发。IL-1具有亚型IL-1α和IL-1β，二者都以无活性形式被生物合成，并通过蛋白酶的切割变成活性形式。负责IL-1β的活化的酶被称作天冬氨酸特异性半胱氨酸蛋白酶（Caspase）-1 (也称作白介素-1β-转化酶 (ICE))。因而，抑制该ICE的物质可以治疗、改善或预防归因于IL-1的疾病、病理学状况、异常状况、疼痛、不利征状等。
现有技术公开了用作TACE 抑制剂的源自海巴戟（Morinda citrifolia L）树的成分 (专利文件1)。也已知Cbz-Val-Ala-(OMe)-氟甲基酮作为ICE 抑制剂 (专利文件2)。但是，这些成分不容易得到，且即使可得到，也具有摄取的容易性、安全性等问题。
专利文件1: 日本专利公开 No. 2007-016015 A
专利文件2: 日本专利公开 No. 11-302192 A (1999)。
发明内容
本发明的一个目的是，提供抗炎症组合物，其具有高效力、不会造成相关的副作用、容易摄取，且因为它的低成本和高安全性，也可以长时间给药。
作为对具有肿瘤坏死因子-转化酶 (TACE)-抑制作用的物质和具有天冬氨酸特异性半胱氨酸蛋白酶-1 (ICE)-抑制作用的物质的集中搜索的结果，发明人已经发现，具有特定序列的肽具有TACE-抑制活性和ICE-抑制活性，由此完成了本发明。
因而，本发明包括下述发明:
(1) 包含由下式表示的氨基酸序列的肽:
pyroGlu-(X)n-A或其盐，其中X是相同的或不同的，且各自独立地是Gln、Asn或Pro；A表示Gln、Asn、Leu、Ile、Met、Val或Phe；且n表示0-2的整数；
(2) 根据(1)的肽或其盐，其中X表示Gln或Pro；A是Gln、Leu、Met、Val或Phe；且n表示0或1；
(3)根据(2)的肽或其盐，其中所述肽选自：pyroGlu-Leu、pyroGlu-Val、pyroGlu-Met、pyroGlu-Phe、pyroGlu-Gln-Gln和pyroGlu-Pro-Gln；
(4) 一种抗炎症组合物，其包含根据(1)至(3)中任一项的至少一种肽或其盐作为活性成分；
(5) 根据(4)的组合物，其中所述组合物通过抑制肿瘤坏死因子-转化酶和/或天冬氨酸特异性半胱氨酸蛋白酶-1用来抑制炎症；
(6) 根据(4)或(5) 的组合物，其中所述组合物用于预防、改善或治疗其中涉及肿瘤坏死因子和/或白介素的炎症疾病或病症；和
(7) 根据(4)至(6)中任一项的组合物，其中所述组合物是食物形式。
根据本发明，提供了抗炎症组合物，其具有比使用常规药物制品的治疗更高的安全性，且可以以简单的方式摄取。
具体实施方式
下面具体描述本发明的优选实施方案。
发明人已经发现，包含由pyroGlu-(X)n-A表示的氨基酸序列的肽或其盐 (该肽在下文中有时称作本发明的肽)具有抑制肿瘤坏死因子-转化酶和/或天冬氨酸特异性半胱氨酸蛋白酶-1的活性，且具有抗炎症作用。在这里，pyroGlu表示焦谷氨酸；X独立地是Gln (谷氨酰胺)、Asn (天冬酰胺)或Pro (脯氨酸)、优选Gln或Pro；A表示Gln、Asn、Leu (亮氨酸)、Ile (异亮氨酸)、Met (甲硫氨酸)、Val (缬氨酸)或Phe (苯丙氨酸)、优选Gln、Leu、Met、Val或Phe；且n表示0、1或2、优选0或1。由该式表示的肽的实例包括pyroGlu-Leu、pyroGlu-Val、pyroGlu-Met、pyroGlu-Phe、pyroGlu-Gln-Gln和pyroGlu-Pro-Gln。
焦谷氨酸是它的γ-位酰胺基和α-位氨基被环化的谷氨酸。本发明的肽可以是天然或重组蛋白的部分水解物，通过化学合成方法或基因工程技术制备的肽，或它们的组合。
构成本发明的肽的氨基酸可以是D-型、L-型或DL-型 (外消旋形式) 氨基酸；但是，它们优选地是L-型氨基酸。当通过天然蛋白的部分水解来制备本发明的肽时，组成氨基酸都是L-型氨基酸。当通过化学合成方法来制备本发明的肽时，可以制备这样的肽，它的组成氨基酸都是L-型或D-型氨基酸，或其中任意氨基酸是L-型氨基酸，且剩余氨基酸是D-型氨基酸；两种肽都包括在本发明内。
通过氨基酸分析方法，可以测定本发明肽的组成。因为酸性水解方法被广泛地用于将焦谷氨酸和谷氨酰胺两者转化成谷氨酸，优选地使用这样的方法，其包括，在使用对它们特异性的酶进行分解后，定量谷氨酰胺和焦谷氨酸。当所述肽是合成肽时，可以从在合成中使用的每种氨基酸的量、比例等，确定所述组成。
本发明肽的盐没有特别限制，条件是，它是药学上可接受的盐或食物；其实例包括酸加成盐和碱加成盐。酸加成盐的实例包括一个无机酸（诸如盐酸、硫酸、硝酸和磷酸）的盐和与有机酸（诸如醋酸、苹果酸、琥珀酸、酒石酸和柠檬酸）的盐。碱加成盐的实例包括与碱金属（诸如钠和钾）的盐、与碱土金属（诸如钙和镁）的盐和与胺（诸如铵和三乙胺）的盐。
当通过天然蛋白的部分水解来制备本发明的肽时，可以适当地采用一种众所周知的方法作为水解该蛋白的方法。其具体实例包括使用酸的水解方法和使用蛋白酶的水解方法。
在水解中使用的天然蛋白可以是任意可得到的蛋白；但是，优选地是已经确认了安全性的蛋白。这样的蛋白的实例包括源自动物的肉、皮肤、奶、血液等的动物性蛋白，和源自谷类（诸如稻谷和小麦）和水果（诸如美洲柿和桃子）的植物性蛋白。在它们中，已知诸如在小麦种子中所含的谷蛋白等蛋白富含谷氨酰胺，且优选作为制备本发明的肽的原料。
使用酸水解蛋白的方法可以采用常规方法。所述酸可以是诸如硫酸、盐酸、硝酸、磷酸和亚硫酸的无机酸，诸如草酸、柠檬酸、醋酸和甲酸等有机酸等的有机酸。
当使用酸进行水解时，需要根据该酸的类型和当量浓度，适当地调节水性介质中的该蛋白的浓度；优选地，通常在调节它的浓度至1.0-80%（按质量计算）之后，处理该蛋白。
当使用蛋白酶水解该蛋白时，可以在水性介质中使一种或多种蛋白酶作用于蛋白，以形成水解物。优选的是使用单独的酸性蛋白酶的方法，和可以有效地实施水解的使用酸性蛋白酶和中性蛋白酶或碱性蛋白酶的方法。当将植物性蛋白用作该蛋白时，在植物中包含的淀粉或纤维有时对蛋白酶作用或在纯化中造成妨碍。在这样的情况下，优选地在使上述蛋白酶起作用之前和之后，或与所述蛋白酶一起，使诸如淀粉酶或纤维素酶的糖分解酶起作用。
用于纯化这样得到的蛋白水解物的方法包括，过滤不溶物的方法，使用含水的醇等进行分级(萃取)的方法，和通过凝胶过滤色谱法、高效液相色谱法(HPLC)或自动聚焦进行纯化的方法。
当通过化学合成方法制备本发明的肽时，可以使用液相合成方法和固相合成方法中的任一种。优选的是这样的固相合成方法，其包括，将氨基酸或肽的C-末端通过连接基团固定到固相支持物上，并相继向N-端延伸氨基酸。当采用固相合成方法时，肽合成仪(例如，来自Shimadzu的PSSM8，或来自ABI的433A型)也可以用于合成。
用于固相合成的固相支持物可以是这样的任意固相支持物，其具有结合作为本发明的肽的C-末端氨基酸的Gln、Asn、Leu、Ile、Met、Val或Phe的羧基的性质；其实例包括二苯甲基胺树脂 (BHA树脂), 氯甲基树脂、氧甲基树脂、氨基甲基树脂、甲基二苯甲基树脂 (MBHA树脂)、乙酰胺基甲基树脂 (PAM树脂)、对-烷氧基苄基醇树脂(Wang树脂)、4-氨基甲基苯氧基甲基树脂和4-羟甲基苯氧基甲基树脂。
作为合成的一个具体实例，下面将显示制备pyroGlu-Gln-Gln作为本发明的肽的试验。
提供谷氨酰胺 (Gln)作为C-末端氨基酸，其中羧基被保护，随后与其缩合作为第二氨基酸的谷氨酰胺 (Gln)，其中该氨基被诸如Boc (叔丁氧羰基)基团或Fmoc (9-芴基甲氧基羰基)基团等保护基保护，且羧基被活化。然后从得到的Gln-Gln二肽去除N-末端谷氨酰胺的氨基的保护基，随后与其缩合作为第三氨基酸的谷氨酰胺 (Gln)，其中氨基被诸如Boc (叔丁氧羰基)基团或Fmoc (9-芴基甲氧基羰基)基团等保护基保护，且羧基被活化。当使用固相合成方法时，只需要使C-末端谷氨酰胺的羧基结合至固相支持物，以替代保护羧基。
可以如下进行羧基活化：通过使羧基与多种试剂中的任一种反应，以形成对应的酰氯、酸酐或混合的酸酐、叠氮化物或活性酯诸如-ONp或-OBt。肽缩合反应也可以在缩合剂和外消旋化抑制剂（诸如碳二亚胺试剂(例如，二环己基碳二亚胺 (DCC)、水溶性的碳二亚胺(WSCD)或N,N'-羰基二咪唑（carbodiimidazole）)、四乙基焦磷酸盐或1-羟基苯并三唑 (HOBt)）存在下进行。
在合成反应结束后，对于该固相合成方法，可以从固相支持物分离得到的肽，去除所有保护基，随后洗涤，以提供三肽Gln-Gln-Gln，它是粗肽形式。随后，通过环化，可以将在N-末端的谷氨酰胺转化成焦谷氨酸，以提供本发明的肽。所述环化在水溶液中逐渐进行；但是，通过升高温度，可以加快它的速度。通过对作为N-末端氨基酸的焦谷氨酸进行缩合反应，也可以制备所述肽。
当使用液相合成方法时，可以以与固相合成方法相同的方式合成该肽，例外是，C-末端氨基酸未结合至固相支持物。通过使用诸如高效液相色谱法(HPLC)等众所周知的方法进行适当纯化，可以将这样得到的含有本发明的肽的粗肽制成高度纯化的肽。
如上所述，对于肽的化学合成方法，可以相继使氨基酸进行缩合，并从C-末端向N-末端延伸，以合成具有希望的氨基酸序列的本发明的肽。在这里，也可以使用L-或D-型氨基酸来合成肽，其中任意氨基酸是L-型氨基酸，且剩余氨基酸是D-型氨基酸。
这样得到的本发明的肽具有抑制肿瘤坏死因子-转化酶 (TACE)和/或天冬氨酸特异性半胱氨酸蛋白酶-1 (ICE)的活性。
可以通过下述方法测定TACE-抑制活性：包括使TACE与无活性的TNF-α反应并测定得到的TNF-α的生成量和活性的方法，包括使TACE与TACE-特异性的底物反应并测定得到的产物的量的方法等。还可以使用可商业得到的测定试剂盒(来自Merck)。
可以通过下述方法测定ICE-抑制活性：包括使ICE与无活性的IL-1β反应并测定得到的IL-1β的生成量和活性的方法，包括使ICE与ICE-特异性的底物反应并测定得到的产物的量的方法等。还可以使用可商业得到的测定试剂盒(来自R&D Systems)。
TACE参与肿瘤坏死因子(TNF)、尤其是TNF-α的活化，已知所述因子是由炎症细胞释放，并造成各种细胞毒性反应、免疫反应和炎症反应。因而，具有抑制该TACE的活性的本发明的肽，具有抑制炎症、尤其是归因于肿瘤坏死因子(优选TNF-α)的炎症的活性。ICE参与白介素、尤其是IL-1β的活化，白介素是刺激前列腺素、胶原酶和磷脂酶的生产、嗜碱性粒细胞和嗜酸性粒细胞的去粒、和嗜中性粒细胞的活化的主要炎症细胞因子，并引起局部的或全身的炎症反应。因而，具有抑制该ICE的活性的本发明的肽，具有抑制炎症、尤其是归因于白介素 (优选IL-1、更优选IL-1β) 的炎症的活性。
为了本发明的目的，炎症是由活体对损伤或刺激（归因于物理的、化学的或生物的因素）的免疫应答引起的现象。它经常造成发炎组织处的疼痛、热觉、发红、和肿胀，有时进一步导致发炎组织的功能减退或功能丧失。
因而，本发明也涉及抗炎症组合物，尤其是通过抑制TACE和/或ICE来抑制炎症的抗炎症组合物，其含有本发明的肽作为活性成分 (在下文中有时称作本发明的组合物)。本发明的组合物也可以用作用于预防、改善或治疗其中涉及肿瘤坏死因子(尤其是TNF-α)和/或白介素 (尤其是IL-1β)的炎症疾病或病症的组合物。本发明的组合物可以仅含有一种或多种本发明的肽。本发明也涉及抑制炎症的方法，尤其是通过抑制TACE和/或ICE来抑制炎症的方法，所述方法包括，将本发明的肽或组合物给药于哺乳动物。本发明也涉及用于预防、改善或治疗其中涉及肿瘤坏死因子(尤其是TNF-α)和/或白介素 (尤其是IL-1β)的炎症疾病或病症的方法，所述方法包括将本发明的肽或组合物给药于哺乳动物。
其中涉及肿瘤坏死因子和/或白介素的炎症疾病或病症的具体实例包括，关节炎、炎症、风湿病、炎性肠病、克罗恩病、反流性食管炎、肺气肿、哮喘、慢性阻塞性肺疾病、阿尔茨海默病、干燥综合征、恶病质、花粉病、过敏性反应、食物过敏、变应性接触性过敏、接触性皮炎、癌症、组织溃疡形成、再狭窄、牙周疾病、大疱性表皮松解、骨质疏松症、移植排斥、疼痛诸如植入疼痛、疼痛诸如人工关节痛、动脉硬化、主动脉/动脉瘤、充血性心力衰竭、心肌梗死、脑缺血、缺血再灌注症状、子宫内膜异位症、全身过敏、神经退化性疾病、自身免疫性损伤、亨廷顿病、帕金森病、偏头痛、抑郁、破骨细胞病、脑膜炎、神经性疼痛、肌萎缩侧索硬化症、多发性硬化症、皮肥厚、银屑病、眼部血管生成、结膜疾病、角膜疾病、角膜愈合、巩膜炎、黄斑变性、异常伤口愈合、烧伤、糖尿病、肿瘤浸润、肿瘤增殖、肿瘤转移、AIDS、败血症和脓毒性休克。本发明的组合物可特别有效地预防、改善和治疗风湿病。
已知过劳、慢性疲劳综合征、肌肉疼痛等是其中涉及肿瘤坏死因子和/或白介素的其它疾病或病理状况。本发明对它们也是特别有效的。
根据本发明，疾病或病症的预防包括抑制和延迟疾病或病症的发生，也包括在疾病或病症发展之前阻止、以及在治疗后对疾病或病症的复发的阻止。根据本发明，疾病或病症的治疗包括：治愈疾病或病症，改善它们的症状，和抑制症状的进展。抗炎症活性是指抑制炎症的活性，炎症的抑制包括炎症的预防和治疗，且包括抑制炎症、抑制炎症的进展、治愈炎症和改善炎症。
为了本发明的目的，哺乳动物是指恒温动物；其实例包括灵长类动物诸如人和猴，啮齿类动物诸如小鼠、大鼠和兔，宠物动物诸如狗和猫，和家养动物诸如牛、马和猪。本发明的组合物适合给药给灵长类动物，尤其是人。特别优选地，将本发明的组合物给药于具有炎症的人、已经诊断为具有炎症的人、具有发展炎症的可能性的人、和需要预防炎症的人。
在通常的情况下，按照肽质量计，在0.01-20 g/天/成年人、优选0.1-10 g/天/成年人的范围，施用本发明的组合物。当通过天然蛋白的部分水解来制备在本发明中使用的肽时，它的剂量也可以进一步增加，因为它是源自天然产物的、具有高安全性的肽。优选地，适当增加或减小剂量，同时观察其效力等。日剂量可以一次性给药或摄取，但是优选地分数份给药。
本发明的组合物的形式没有特别限制；例如，它可以制成药物组合物或食物(包括饲料)。
当制成药物组合物时，通常将本发明的组合物制成含有本发明的肽和药学上可接受的载体的制剂。药学上可接受的载体通常是指填充剂、稀释剂、包封材料等，它们是无活性的、无毒的固体或液体，且不与作为活性成分的本发明的肽反应；其实例包括溶剂或分散介质，诸如水、乙醇、多元醇 (例如，甘油、丙二醇和液体聚乙二醇)、它们的合适的混合物、和植物油。
药物组合物的剂型没有特别限制，且可以是任意剂型，包括用于口服给药的剂型（诸如片剂、丸剂、颗粒、粉尘制剂、细颗粒、粉剂、胶囊剂、糖浆剂、饮用制剂、溶液、栓剂和流食）和用于肠胃外给药的剂型（诸如舌下片剂、喷鼻剂和注射溶液）。
除口服给药之外，本发明的组合物的给药方法包括通常用于药物给药的给药方法：诸如静脉内给药、肌肉内给药和皮下给药。也可以采用包括经除胃肠道之外的粘膜吸收的给药方法，诸如直肠、舌下和鼻内给药。在这里，该药物组合物可以以例如栓剂、舌下片剂或喷鼻剂的形式给药。
本发明的肽在药物组合物中的含量随其形式而变化；但是，它通常是0.001%至99%（按质量计算），优选0.01%至90%（按质量计算），更优选1%至85%（按质量计算），甚至更优选5%至80%（按质量计算），基于干重计算。优选地，可以控制每日剂量，从而达到上述每个成年人的每日摄取剂量。
当本发明的组合物制成食物时，其形式没有特别限制。所述食物包括饮料，也包括保健食品和功能食品。保健食品和功能食品可以制成不同制剂的形式，诸如片剂、丸剂、颗粒、粉尘制剂、细颗粒、粉剂、胶囊剂、糖浆剂、饮用制剂、溶液和流食。可以以与上述药物组合物相同的方式，生产制剂形式的食物。例如，在加入合适的赋形剂(例如，淀粉、加工过的淀粉、乳糖、葡萄糖或水)后，可以使用常规方式来生产。食物的具体实例进一步包括咖啡饮料、茶饮料、含有果汁的饮料、软饮料、乳饮料、黄油、蛋黄酱、起酥油、人造黄油、各类沙拉酱、面包、面条、煮饭、面食、调味料、糕饼、饼干、巧克力、糖果、口香糖、各类调味料、以及各类饮食产品。通过将本发明的肽加入这样的食物中，可以制备食物形式的本发明的组合物。
本发明的肽在本发明的食物中的含量随食物形式而变化。它通常是0.01%至80%（按质量计算），优选0.1%至75%（按质量计算），更优选1%至70%（按质量计算），甚至更优选5%至70%（按质量计算），基于干重计算。因为本发明的肽具有高安全性，也可以进一步增加它的含量。每日摄取量可以一次性摄取，也可以分数份摄取。优选地，可以控制摄取量，从而达到上述每个成年人的每日摄取量。
摄取具有抗炎症作用的本发明的肽或其盐或含有其的本发明的组合物，可以抑制炎症，且特别地期望具有预防、改善或治疗其中涉及肿瘤坏死因子和/或白介素的炎症疾病或病症的作用。
本发明的组合物可以含有用于生产药品、食物和饲料的各种添加剂。另外可以共同存在各种活性物质。这样的添加剂和活性物质的实例包括各种油脂、生药、氨基酸、多元醇、天然产生的聚合物、维生素、矿物质、膳食纤维、表面活性剂、纯净水、赋形剂、稳定剂、pH调节剂、抗氧化剂、甜味剂、调味成分、酸化剂、着色剂和香料。本发明的肽可以与一种或多种具有抗炎症活性的其它活性成分混合地或组合地给药。因而，除本发明的肽之外，本发明的抗炎症组合物可以包含具有抗炎症活性的其它活性成分。
各种油脂的实例包括植物油脂（诸如大豆油、红花油和橄榄油）和动物油脂（诸如牛油和沙丁鱼油）。
生药的实例包括牛黄、地黄、枸杞、蜂王浆、党参和鹿茸。
氨基酸的实例包括半胱氨酸、亮氨酸和精氨酸。
多元醇的实例包括乙二醇、聚乙二醇、丙二醇、甘油和糖醇。糖醇的实例包括山梨糖醇、赤藓醇、木糖醇、麦芽糖醇和甘露糖醇。
天然产生的聚合物的实例包括阿拉伯树胶、琼脂、水溶性玉米纤维、明胶、黄原胶、酪蛋白、谷蛋白或谷蛋白水解物、卵磷脂和糊精。
各种维生素的实例除了维生素C (抗坏血酸)、维生素B族和维生素E (生育酚)之外，包括维生素A、D和K和核黄素丁酸酯，以及。维生素B族包括各种维生素B复合物，诸如维生素B1、维生素B1衍生物、维生素B2、维生素B6、维生素B12、生物素、泛酸、烟酸和叶酸。维生素B1及其衍生物包括具有维生素B1的生理活性的所有化合物，诸如硫胺素或其盐、二硫胺、呋喃硫胺或其盐、地赛硫胺、双丁硫胺、双苯酰硫胺、苯磷硫胺、二硫化磷酸硫胺、赛内酯硫胺、辛硫胺和丙硫硫胺、
矿物质的实例包括钙、镁、锌和铁。
膳食纤维的实例包括树胶、甘露聚糖、果胶、半纤维素、木质素、β--葡聚糖、木聚糖和阿拉伯木聚糖。
表面活性剂的实例包括甘油脂肪酸酯、失水山梨糖醇脂肪酸酯和蔗糖脂肪酸酯。
赋形剂的实例包括蔗糖、葡萄糖、玉米淀粉、磷酸钙、乳糖、糊精、淀粉、微晶纤维素和环糊精。
具有抗炎症活性的其它活性成分的实例包括海巴戟-衍生的成分、Cbz-Val-Ala-(OMe)-氟甲基酮、甘草、甘草次酸、桦木醇、熊果酸、蜂胶、芦荟、黄褥花果、桉树提取物、母菊提取物、黄柏皮、樟脑、颠茄、吲哚美辛、布洛芬、吡罗昔康、水杨酸、双氯芬酸、酮洛芬、萘普生和吡罗昔康。
除了上述以外，可以掺混下述作为添加剂：例如，牛磺酸、谷胱甘肽、肉碱、肌酸、辅酶Q、α-硫辛酸、葡萄糖醛酸、葡醛内酯、茶氨酸、γ-氨基丁酸、辣椒素、各种有机酸类、黄酮类、多酚类、儿茶素类、黄嘌呤衍生物、不可消化的寡糖（诸如果糖-寡糖）或聚乙烯吡咯烷酮。根据添加剂类型和希望的摄取量，适当地确定这些添加剂各自的掺混量；但是，它通常在0.01- 30%（按质量计算）、优选0.1-10%（按质量计算）的范围。
将参考下述实施例，具体描述本发明的肽和组合物的生产实施例和试验实施例。但是，本发明不限于这些实施例。
实施例
生产实施例1: pyroGlu-Gln-Gln的合成
使用433A型肽 合成仪 (来自ABI)，通过固相方法，合成PyroGlu-Gln-Gln。
使用2 g Boc-Gln-Pam树脂作为原料，并采用受保护的氨基酸Boc-Gln和Boc-Glu (OBzl)，以下述方式进行自动合成。
(1) 从Boc-Gln-Pam树脂去除Boc基团的反应
(2) 洗涤
(3) 活化Boc-Gln
(4) 将活化的Boc-Gln加入Gln-Pam树脂，进行缩合
(5) 洗涤
(6) 乙酰化未反应的N-末端氨基
(7) 洗涤
(8) 从Boc-Gln-Gln-Pam树脂去除Boc基团的反应
(9) 洗涤
(10) 活化Boc-Glu(OBzl)
(11) 将活化的Boc-Glu(OBzl)加入Gln-Gln-Pam树脂，进行缩合
(12) 洗涤
(13) 乙酰化未反应的N-末端氨基
(14) 洗涤
(15) Boc-Glu(OBzl)-Gln-Gln-Pam树脂
通过用三氟醋酸-二氯甲烷 (50:50)处理20分钟，去除Boc基团。使用二氯甲烷，重复所有洗涤步骤各3次。通过如下进行缩合：在DCC和HOBt存在下，以5倍当量的树脂-结合的氨基，加入Boc-保护的氨基酸，随后反应60分钟。
从肽合成仪移出得到的Boc-Glu(OBzl)-Gln-Gln-Pam树脂，并转移至另一个容器。向其中加入1 ml茴香硫醚和0.5 ml乙二硫醇/g树脂，然后在室温搅拌该混合物10分钟。然后，在冰冷却下，缓慢加入10 ml氟化氢，然后将其搅拌30分钟，随后在减压下蒸馏除去氟化氢。向该容器装入100 ml冷的乙醚，将得到的物质搅拌1分钟，以沉淀出肽和树脂。通过用Polyfron过滤器PF060 (来自Advantec)过滤，收集得到的物质，并用冷乙醚(-40℃)洗涤。将肽溶于约30 ml三氟醋酸中，然后将它逐滴加入300 ml预先提供的冷乙醚中，以再次沉淀出肽。通过用3 μm-孔PTFE膜 (来自Advantec) 过滤，收集得到的物质，并用冷乙醚(-40℃)洗涤。将肽溶于2N 醋酸中，然后冻干。从2.35 g受保护的肽-Pam-树脂，得到粗肽(1.21 g)。将粗肽溶于水中，并在60℃保持6小时以环化成焦谷氨酸，随后冻干。
在下述条件下，使用HPLC，纯化得到的粗肽。
柱: Inertsil ODS-3, φ20×250 mm (来自GL Sciences)
流动相: 从0.1%三氟醋酸至在0.1%三氟醋酸中的35%乙腈的梯度
流速: 10 mL/min
检测器: 紫外线分光光度计, 210 nm
温度: 40℃
分离HPLC色谱图的主峰，并使用肽测序仪，分析该分离产物的氨基酸序列。从1 g粗肽，得到0.88 g纯化的pyroGlu-Gln-Gln肽。
生产实施例2: pyroGlu-Leu的合成
使用Boc方法，通过液相方法，合成PyroGlu-Leu。
(1) Boc-pyroGlu和HCl Leu-OtBu的缩合
将HCl Leu-OtBu (390 mg)导入茄形烧瓶中，溶于5 ml DMF中，并用冰冷却，然后向其中加入0.124 ml 三乙胺。随后，向其中加入400 mg Boc-pyroGlu-OH、470 mg HOBt和367 mg WSCD HCl，然后在冰冷却下，将它们搅拌12小时，进行缩合反应。在反应结束后，在减压下蒸馏除去DMF，将残余物溶于醋酸乙酯中。然后，用5%碳酸氢钠水溶液、10%柠檬酸水溶液、水和饱和盐水依次洗涤醋酸乙酯，并将得到的物质用无水硫酸钠干燥。滤出硫酸钠，并在减压下浓缩滤液。向得到的残余物中加入醚-己烷，以固化并收集Boc-pyroGlu-Leu-OtBu。产量是609 mg (88%)。
(2) 去保护
将上面得到的Boc-pyroGlu-Leu-OtBu (600 mg)引入茄形烧瓶中，然后向其中加入5 ml三氟醋酸进行溶解，随后在冰冷却下进行去保护反应1小时。使用N2气去除三氟醋酸，并通过加入醚，固化去保护的肽，然后通过过滤进行收集。将得到的固体溶于4N HCl/二 
烷中，然后向其中加入醚，进行重新固化，然后通过过滤进行收集。产量是220 mg (53%)。
生产实施例3: pyroGlu-Val的合成
使用209.7 mg HCl H-Val-OtBu作为原料，以与生产实施例2相同的方式，合成PyroGlu-Val。缩合反应的产量是326.6 mg (85%)，去保护的肽的产量是205.0 mg (91%)。
生产实施例4: pyroGlu-Met的合成
使用241.8 mg HCl H-Met-OtBu作为原料，以与生产实施例2相同的方式，合成PyroGlu-Met。缩合反应的产量是208.3 mg (50%)，去保护的肽的产量是90.3 mg (60%)。
生产实施例5: pyroGlu-Phe的合成
使用257.8 mg HCl H-Phe-OtBu作为原料，以与生产实施例2相同的方式，合成PyroGlu-Phe。缩合反应的产量是242.9 mg (56%)，去保护的肽的产量是103.1 mg (59%)。
生产实施例6: pyroGlu-Gln-Gln的合成
使用Fmoc方法，通过液相方法，合成PyroGlu-Gln-Gln。
(1) Fmoc-Gln(Trt)-Gln-OtBu的合成
将HCl Gln-OtBu (1.15 g)导入茄形烧瓶中，溶于5 ml DMF中，并用冰冷却，然后向其中加入0.74 ml 三乙胺。随后，向其中加入2.94 g Fmoc-Gln(Trt)-OH、1.3 g HOBt和1.01 g WSCD HCl，然后在冰冷却下，将它们搅拌12小时，进行缩合反应。在反应结束后，在减压下蒸馏除去DMF，将残余物溶于醋酸乙酯中。然后，用5%碳酸氢钠水溶液、10%柠檬酸水溶液、水和饱和盐水依次洗涤醋酸乙酯，并将得到的物质用无水硫酸钠干燥。滤出硫酸钠，并在减压下浓缩滤液。向得到的残余物中加入醚-己烷，以固化并收集Fmoc-Gln(Trt)-Gln-OtBu。产量是3.51 g (92%)。
(2) 从Fmoc-Gln(Trt)-Gln-OtBu 去除Fmoc基团
将Fmoc-Gln(Trt)-Gln-OtBu (1.12 g)引入茄形烧瓶中，然后在冰冷却下向其中加入7 ml 1M NaOH水溶液。由于该混合物形成白色浑浊，向其中加入甲醇进行溶解，使溶液在0℃下反应2小时。加入柠檬酸进行中和后，将水加入真空浓缩得到的白色固体中，然后搅拌，以得到树胶状固体。将该固体上硅胶柱，使用氯仿作为溶剂，分离希望的成分，并使用醚固化。产量是590 mg (73%)。
(3) Boc-pyroGlu-Gln(Trt)-Gln-OtBu的合成
将H-Gln(Trt)-Gln-OtBu (580 mg)引入茄形烧瓶中，溶于5 ml DMF中，并用冰冷却，然后向其中加入156 μL三乙胺。随后，向其中加入232 mg Boc-pyroGlu-OH、273 mg HOBt和213 mg WSCD HCl，然后在冰冷却下将其搅拌12小时，进行缩合反应。在减压下蒸馏除去DMF，将残余物溶于醋酸乙酯中。然后，用5%碳酸氢钠水溶液、10%柠檬酸水溶液、水和饱和盐水依次洗涤醋酸乙酯，并将得到的物质用无水硫酸钠干燥。滤出硫酸钠，并在减压下浓缩滤液。使用真空泵将得到的残余物减压，以去除溶剂。产量是509.3 mg (64%)。
(4) 去保护
将Boc-pyroGlu-Gln(Trt)-Gln-OtBu (760 mg)引入茄形烧瓶中，然后向其中加入10 ml三氟醋酸进行溶解，随后在冰冷却下反应4小时。使用N2气去除三氟醋酸，并通过加入醚，固化去保护的肽。通过离心收集固体，并通过再次加入醚来悬浮。离心悬浮液，以收集固体。重复该操作3次，以得到粗肽。产量是445 mg (100%)。
(5) pyroGlu-Gln-Gln的纯化
上面得到的粗肽含有水不溶性的杂质。因而，将粗肽悬浮于水中，通过过滤器收集滤液。向滤液中引入2 ml 1M盐酸，然后将其冻干。将醚加入冻干产物，以固化本发明的肽，收集固体，然后干燥。终产量是256 mg (63%)。
生产实施例7: pyroGlu-Pro-Gln的合成
使用生产实施例6的Fmoc方法，通过液相方法，合成PyroGlu-Pro-Gln。产量是174 mg (49%)。
生产实施例8: 从天然蛋白提取pyroGlu-Gln-Gln、pyroGlu-Gln、pyroGlu-Leu和pyroGlu-Ile
(1) 将离子交换水(9,700 kg)、无水柠檬酸 (38 kg)和小麦谷蛋白 (1,500 kg) (活性谷蛋白，来自Weston Foods Limited)装入反应器中，并在45℃下温热。然后，向其中加入2.2 kg 蛋白酶 (“Protease M Amano”，来自Amano Pharmaceutical Co., Ltd.)和1.1 kg 淀粉酶 (“Liquefying Enzyme T”，来自Hankyu Bioindustry Co., Ltd.)，在45℃下水解5小时。随后，使用25%氢氧化钠水溶液，将该液体调节至pH 4.4-4.5，并在该状态保持7小时，进行酶处理。
(2) 随后，在80℃维持液体20分钟，以灭活蛋白酶。此后，将液体冷却至65℃，然后向其中加入0.5 kg 淀粉酶 (“Liquefying Enzyme T”，来自Hankyu Bioindustry Co., Ltd.) ，以水解在小麦谷蛋白中含有的淀粉和纤维，随后通过在90℃维持液体20分钟，灭活淀粉酶。
(3) 接着，将液体冷却至10℃或更低，然后再次加热至55℃。向其中加入活性炭(“Takecoal”，来自Takeda Pharmaceutical Company Limited) (100 kg)，然后在55℃下搅拌30分钟。
(4) 将液体温度调至45℃，加入助滤剂 (“Radiolite”，来自Showa Chemical Industry Co., LTD.)。使用加压过滤装置进行过滤，回收7,000升(7 m3)滤液。
(5) 在减压下浓缩在上面(4)中回收的滤液，通过使用板式加热器在110℃下加热20 秒，进行灭菌，然后冷却至55℃。
(6) 在160℃的鼓风温度和80℃的排气温度的条件下，使用喷雾干燥器喷雾干燥在上面(5)中得到的液体，得到约1,000 kg粉末状小麦谷蛋白水解物。
(7) 使用凝胶过滤方法，从在上面(6)中得到的粉末分离分子量为1,000或更小的级分，并使用HPLC进一步纯化。通过HPLC，基于以与生产实施例1相同的方式得到的合成的pyroGlu-Gln-Gln、pyroGlu-Gln、pyroGlu-Leu和pyroGlu-Ile，收集在相同条件下表现出相同保留时间的部分。结果，从800 kg粉末状小麦谷蛋白水解物，分别得到4.5 kg、1.6 kg、0.9 kg和0.7 kg肽。
(8) 使用肽测序仪，分析纯化的肽的氨基酸序列。结果，发现该肽具有序列pyroGlu-Gln-Gln、pyroGlu-Gln、pyroGlu-Leu和pyroGlu-Ile。
实施例 1: 片剂的生产
混合在生产实施例8中得到的pyroGlu-Leu肽 (84 g)、10 g微晶纤维素 (来自Asahi Kasei Corporation)、和5 g 聚乙烯吡咯烷酮 (来自BASF) ，然后向其中加入3 ml 乙醇，随后根据常规方法，通过湿法生产颗粒。干燥得到的颗粒，然后向其中加入1.1 g 硬脂酸镁，制备用于压片的颗粒粉末。使用压片机压制粉末，生产100片，各自的重量是1 g (每片的pyroGlu-Gln含量是0.84 g)。
实施例 2: 糖浆剂制剂的生产
煮沸净化水(400 g)，然后在搅拌下向其中加入750 g蔗糖和100 g在生产实施例8中得到的pyroGlu-Leu肽，进行溶解。然后在热状态期间，将该溶液渗滤。向产物中加入净化水至1,000 mL总量，生成糖浆剂制剂(每100 ml 糖浆剂制剂的pyroGlu-Leu含量是10 g)。
实施例 3: 颗粒制剂的生产
混合在生产实施例8 中得到的PyroGlu-Leu肽(76 g)、13.3 g 乳糖 (来自DMV)、6.7 g微晶纤维素 (来自Asahi Kasei Corporation)和4 g 聚乙烯吡咯烷酮 (来自BASF)，然后向其中加入30 ml 乙醇，随后根据常规方法，通过湿法生产颗粒。干燥后，调整颗粒尺寸，得到颗粒制剂(每10 g 颗粒制剂的pyroGlu-Ile含量是7.6 g)。
实施例 4: 流食的生产
将酪蛋白酸钠 (来自DMV) (40 g)、160 g 麦芽糊精 (来自Sanwa Cornstarch Co., Ltd.)和25 g在生产实施例8中得到的pyroGlu-Leu肽加入在约65℃的750 ml净化水，进行溶解。随后，向其中加入5 g维生素混合物和5 g矿物混合溶液（其包含钠、钾、钙、镁、氯、铁、磷、铜、锌、锰和硫）。将混合物装入均质混合器 (来自Tokushu Kika Kogyo Co., Ltd.)，并在约8,000 rpm大致乳化15分钟。将得到的乳剂冷却至约20℃，然后向其中加入香料，随后在量筒中稀释至终量1,000 mL。将乳剂(230 g)装入小袋，并在用氮气排空的同时密封。在121℃灭菌液体15分钟，得到浓缩的流食 (每230 g 流食的pyroGlu-Ile含量是约5.8 g)。
实施例 5: 面包的生产
将小麦粉(高筋粉) (150 g)与2 g 干酵母混合。单独地，将20 g在生产实施例8中得到的pyroGlu-Gln-Gln肽、20 g糖、3 g盐和6 g脱脂奶粉溶于70 g温水中，向其中加入1个鸡蛋，然后将其充分混合。将得到的物质加入小麦粉中，然后用手充分揉捏。然后，向其中加入约40 g黄油，进一步揉捏，制成20个面包的生面团。随后，在发酵该生面团后，将打散的鸡蛋施加到其表面，然后在180℃烘箱中烘烤约15分钟，制成面包 (每个面包的pyroGlu-Gln-Gln含量是约1 g)。
实施例 6: 意大利面用肉酱的生产
将一份意大利面用肉酱 (150 g)引入平锅中，同时向其中加入5 g在生产实施例8中得到的pyroGlu-Gln-Gln肽，然后加热，制成意大利面用肉酱。将得到的酱装入小袋，并在用氮气排空的同时密封，在121℃灭菌15分钟，得到含有pyroGlu-Gln-Gln肽的意大利面用肉酱。
实施例 7: 日本小麦面条的生产
将15 g在生产实施例8中得到的pyroGlu-Leu肽和15 g盐在150 g水中的分散系，加入300 g小麦粉(普通面粉)，然后将其充分揉捏，并静置。此后，拉伸该生面团，并切成约5 mm的宽度，制成日本小麦面条。在沸水中煮该面条约10分钟。结果，面条表现出良好的外观、味道和质地。每份日本小麦面条含有约5 g pyroGlu-Gln肽。
试验实施例1: TACE-抑制活性的测定
制备1 mg/mL的在上述生产实施例中合成的每种焦谷氨酰肽(pyroGlu-Leu、pyroGlu-Val、pyroGlu-Met、pyroGlu-Phe、pyroGlu-Gln-Gln和pyroGlu-Pro-Gln)的样品，并如下评价TACE-抑制活性。
将每个样品 (10 μL)加入10 μL 1 μmol/L反应底物(TACE 底物(Mac-PLAQAV-Dpa-RSSSR-NH2)，来自Biomol. International LP)、10 μL 10 ng/10 μL 酶溶液 (重组人TACE，来自R&D Systems)、50 μL缓冲液 (50 mmol/L Tris-HCl，pH 9.0，5 μM ZnCl2，0.01%Brij35)、和20 μL蒸馏水，在37℃下反应20分钟。向其中加入10%三氟醋酸至1%终浓度，以终止反应。使用反相高效液相色谱，在下述条件下，分离底物和产物。在320 nm的激发波长和405 nm的测定波长下，荧光测定底物和产物，进行定量。
(色谱条件)
溶液 A: 10%乙腈 (0.1%TFA) / 溶液 B: 80%乙腈 (0.1%TFA)
梯度: 从50%至100%的溶液B
柱: 5C18 AR-II; 4.6 φ × 150
炉温: 30℃
测定波长: 230 nm
结果如下面的表1所示，表示为产物荧光强度与产物和底物的荧光强度之比。
[表1]
| 对照(没有肽) | 100% |
| pyroGlu-Leu | 61% |
| pyroGlu-Pro-Gln | 66% |
| pyroGlu-Gln-Gln, | 70% |
| pyroGlu-Val | 81% |
| pyroGlu-Met | 83% |
| pyroGlu-Phe | 84% |
试验实施例2: ICE-抑制活性的测定
制作1 mg/mL的在上述生产实施例中合成的每种焦谷氨酰肽(pyroGlu-Leu、pyroGlu-Val、pyroGlu-Met、pyroGlu-Phe、pyroGlu-Gln-Gln和pyroGlu-Pro-Gln)的样品，并如下评价ICE-抑制活性。
将每个样品(5 μL)加入10 μl的2,000 μmol/L反应底物(天冬氨酸特异性半胱氨酸蛋白酶-1底物(Ac-Trp-Glu-His-Asp-AMC)，来自Alexis Biochemicals)、5 μL 10 U/μL 酶溶液 (天冬氨酸特异性半胱氨酸蛋白酶-1，来自Biomol. International LP)、60 μL缓冲液(50 mmol/L HEPES，pH 7.4，100 mM NaCl，0.1%CHAPS，1 mM EDTA，10%甘油，和10 mM DTT)和20 μL蒸馏水，在37℃下反应20分钟。向其中加入10%三氟醋酸至1%终浓度，以终止反应。使用反相高效液相色谱，在下述条件下，分离底物和产物。在380 nm的激发波长和460 nm的测定波长下，荧光测定底物和产物，进行定量。
(色谱条件)
溶液 A: 10%乙腈 (0.1%TFA) / 溶液 B: 80%乙腈 (0.1%TFA)
梯度: 从50%至100%的溶液B
柱: 5C18 AR-II; 4.6 φ × 150
炉温: 30℃
测定波长: 230 nm
结果如下面的表2所示，表示为产物荧光强度与产物和底物的荧光强度之比。
[表2]
| 对照(没有肽) | 100% |
| pyroGlu-Leu | 55% |
| pyroGlu-Pro-Gln | 62% |
| pyroGlu-Gln-Gln, | 63% |
| pyroGlu-Val | 74% |
| pyroGlu-Met | 75% |
| pyroGlu-Phe | 72% |
本文引用的所有出版物、专利和专利申请都作为参考文献整体并入本文。
Claims (7)
1. 包含由下式表示的氨基酸序列的肽或其盐:
pyroGlu-(X)n-A，
其中X是相同的或不同的，且各自独立地是Gln、Asn或Pro；A表示Gln、Asn、Leu、Ile、Met、Val或Phe；且n表示0-2的整数。
2. 根据权利要求1的肽或其盐，其中X表示Gln或Pro；A是Gln、Leu、Met、Val或Phe；且n表示0或1。
3. 根据权利要求2的肽或其盐，其中所述肽选自：pyroGlu-Leu、pyroGlu-Val、pyroGlu-Met、pyroGlu-Phe、pyroGlu-Gln-Gln和pyroGlu-Pro-Gln。
4. 一种抗炎症组合物，其包含权利要求1-3中任一项的至少一种肽或其盐作为活性成分。
5. 根据权利要求4的组合物，其中所述组合物通过抑制肿瘤坏死因子-转化酶和/或天冬氨酸特异性半胱氨酸蛋白酶-1用于抑制炎症。
6. 根据权利要求4或5的组合物，其中所述组合物用于预防、改善或治疗其中涉及肿瘤坏死因子和/或白介素的炎症疾病或病症。
7. 根据权利要求4-6中任一项的组合物，其中所述组合物是食物形式。
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| KR102636129B1 (ko) | 2015-02-27 | 2024-02-14 | 주식회사 젬백스앤카엘 | 청력 손상 방어용 펩타이드 및 이를 포함하는 조성물 |
| EP3305802B1 (en) | 2015-05-26 | 2021-05-12 | Gemvax & Kael Co., Ltd. | Anti-inflammatory, anti-fibrotic and wound-healing octapeptides and compositions containing the same |
| KR102638286B1 (ko) | 2015-07-02 | 2024-02-20 | 주식회사 젬백스앤카엘 | 항바이러스 활성 효능을 가지는 펩티드 및 이를 포함하는 조성물 |
| KR20180123512A (ko) | 2016-04-07 | 2018-11-16 | 주식회사 젬백스앤카엘 | 텔로머라제 활성 증가 및 텔로미어 연장 효능을 가지는 펩티드 및 이를 포함하는 조성물 |
| JP7355319B2 (ja) * | 2017-11-24 | 2023-10-03 | 国立研究開発法人理化学研究所 | ＩＬ‐１β及び／又はＩＬ‐６の発現抑制剤を含む、脳内炎症に起因する疲労を予防、及び／又は、改善するための抗疲労組成物とその利用 |
| AU2019245521A1 (en) * | 2018-03-29 | 2020-11-12 | S.I.S Shulov Innovative Science Ltd. | Pharmaceutical compositions for inhibiting inflammatory cytokines |
| CN111875668B (zh) * | 2020-07-29 | 2022-05-27 | 陕西慧康生物科技有限责任公司 | 一类含谷氨酰胺或天冬酰胺的环二肽的合成方法 |
| JP2022130781A (ja) * | 2021-02-26 | 2022-09-07 | 太陽化学株式会社 | グミ組成物及びその製造方法 |
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| IT1172391B (it) * | 1983-12-23 | 1987-06-18 | Polifarma Spa | Composti tirpeptidici contenenti acido piroglutaminico e triptofano,procedimentio di produzione ed applicazioni terapeutiche |
| IT1186733B (it) * | 1985-06-05 | 1987-12-16 | Eniricerche Spa | Composti tripeptidici ad azione ipotensiva |
| IT1244548B (it) * | 1991-02-06 | 1994-07-15 | Poli Ind Chimica Spa | Derivati della 5-oxo-l-prolina e loro applicazioni farmaceutiche |
| US5308753A (en) * | 1992-02-20 | 1994-05-03 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Methods for purifying and detecting IGM antibodies |
| IT1256178B (it) * | 1992-11-30 | 1995-11-29 | Lorenzo Ferrari | Composti ad attivita' terapeutica utili per il trattamento di malattieconnesse ad una carenza di glutatione, procedimento per la loro preparazione e composizioni farmaceutiche che li contengono. |
| US5594106A (en) * | 1993-08-23 | 1997-01-14 | Immunex Corporation | Inhibitors of TNF-α secretion |
| DE19523629A1 (de) * | 1995-06-29 | 1997-01-02 | Merck Patent Gmbh | Verpackungsformteile und Verfahren zu ihrer Herstellung |
| US6716963B1 (en) * | 1998-05-22 | 2004-04-06 | Abbott Laboratories | Peptide antiangiogenic drugs |
| IL137820A (en) * | 2000-08-10 | 2009-06-15 | S I S Shulov Inst For Science | Pharmaceutical composition for topical administration comprising an analgesic peptide |
| PE20030320A1 (es) * | 2001-07-17 | 2003-04-03 | Gruenenthal Chemie | Derivados sustituidos de 4-aminociclohexanol |
| US7381537B2 (en) * | 2003-05-05 | 2008-06-03 | Probiodrug Ag | Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease |
| US8338120B2 (en) * | 2003-05-05 | 2012-12-25 | Probiodrug Ag | Method of treating inflammation with glutaminyl cyclase inhibitors |
| US20070122507A1 (en) * | 2005-05-26 | 2007-05-31 | Palu Afa K | Histone deacetylase and tumor necrosis factor converting enzyme inhibition |
| KR101566036B1 (ko) * | 2007-03-23 | 2015-11-04 | 닛신 파마 가부시키가이샤 | 간질환의 예방 또는 치료용 조성물 |
| WO2009052489A2 (en) * | 2007-10-19 | 2009-04-23 | Alba Therapeutics Corporation | Novel inhibitors of mammalian tight junction opening |
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2008
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- 2008-09-22 KR KR1020117009058A patent/KR20110060940A/ko not_active Application Discontinuation
- 2008-09-22 CN CN200880132041.9A patent/CN102224161B/zh not_active Expired - Fee Related
- 2008-09-22 JP JP2010529553A patent/JP5337809B2/ja not_active Expired - Fee Related
- 2008-09-22 US US13/120,371 patent/US20110183925A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112020366A (zh) * | 2018-04-26 | 2020-12-01 | 志瑞亚新药工业株式会社 | 含有二肽的药物组合物 |
| CN112041328A (zh) * | 2018-04-26 | 2020-12-04 | 志瑞亚新药工业株式会社 | 二肽和含有该二肽的药物组合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2010032322A1 (ja) | 2012-02-02 |
| KR20110060940A (ko) | 2011-06-08 |
| US20110183925A1 (en) | 2011-07-28 |
| JP5337809B2 (ja) | 2013-11-06 |
| WO2010032322A1 (ja) | 2010-03-25 |
| CN102224161B (zh) | 2016-03-30 |
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