CN111201029B - Zag来源肽及其用途 - Google Patents
Zag来源肽及其用途 Download PDFInfo
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- CN111201029B CN111201029B CN201880063919.1A CN201880063919A CN111201029B CN 111201029 B CN111201029 B CN 111201029B CN 201880063919 A CN201880063919 A CN 201880063919A CN 111201029 B CN111201029 B CN 111201029B
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- protein
- peptide
- glu
- lys
- gln
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Abstract
本发明涉及一种来源自ZAG(锌‑α‑2‑糖蛋白)蛋白的肽及其用途。根据本发明的ZAG蛋白肽在急性、慢性和特应性皮炎的动物模型中显示出特应性皮炎的病变缓解，通过降低免疫反应、降低IgE的表达，可用于预防、治疗或改善特应性皮炎等皮肤干燥症、皮肤屏障功能障碍、过敏性疾病、炎症。
Description
技术领域
本发明涉及一种ZAG(锌-α-2-糖蛋白)蛋白来源肽及其用途。
背景技术
位于皮肤最外部的表皮对各种外部物理、化学和过敏性机械刺激起到保护作用，并防止体内水分通过皮肤过度丢失。这种保护功能能够通过由角质形成细胞组成的角质层的正常形成和维持来实现。
角质形成细胞产生天然的保湿因子和诸如神经酰胺、胆固醇和脂肪酸之类的细胞间脂质，因此角质层起着对外界的屏障作用，保留其作为皮肤屏障的功能。
皮肤干燥症被认为是现代社会的主要疾病之一，是由皮肤屏障功能障碍引起的症状之一，因最近的环境污染、如摩天大楼等的干燥环境的增加、社会压力的增加，过度的洗浴文化、皮肤老化等因素而日渐增加，因症状严重而需要治疗的情况也越来越多。特应性皮炎也被认为由皮肤干燥引起，且根本上主要原因是皮肤屏障功能的障碍。
特应性皮炎是一种慢性复发性皮肤病，在婴幼儿中的患病率为20％，在成年人中的患病率为1-3％，是一种由遗传和环境因素引起的免疫性疾病。特应性皮炎患者慢性地感觉皮肤的干燥和严重的瘙痒，并通过各种刺激容易诱发皮炎。在严重的情况下，它会发展成亚急性红斑皮疹并伴有渗出和皮肤增厚地慢性病变。
特应性皮炎的主要病理变化是免疫异常反应和皮肤屏障的异常。由某些过敏原引起的2型辅助性T细胞、树突状细胞、嗜酸性粒细胞等的活动可导致炎症反应，导致皮肤屏障的异常。此外，80％至90％的特应性皮炎患者的血清免疫球蛋白E(免疫球蛋白E)会升高，特别是在伴有过敏性鼻炎或哮喘等呼吸道过敏性疾病时，血清免疫球蛋白E水平较高。
免疫疗法和药物疗法被用于治疗特应性皮炎。使用的典型药物是类固醇、钙调神经磷酸酶抑制剂、免疫调节剂、抗组胺药等。局部药剂类固醇和钙调神经磷酸酶抑制剂具有短期效果，但长时间使用会引起副作用，例如皮肤萎缩和血管舒张。抗组胺药是全身性口服制剂，效果甚微。另外，为了恢复干燥和破坏的皮肤屏障，使用神经酰胺的保湿剂在医药和化妆品领域中被使用。尽管有如此多种药物疗法，特应性皮炎尚未得到适当的治疗方法。
专利文献1(韩国专利申请第10-2017-0028169号)是揭示了ZAG蛋白对皮肤干燥症或皮肤屏障的改善以及其抗过敏用途的发明。本发明发掘了ZAG蛋白中对皮肤干燥症或皮肤屏障改善性和抗过敏性尤其优异的肽，并确认了其效果。
【现有技术文献】
【专利文献】
1.韩国专利申请第10-2017-0028169号。
发明内容
技术问题
本发明旨在提供一种ZAG(锌-α-2-糖蛋白)蛋白来源肽及其用途。
技术方案
本发明的发明人从ZAG蛋白中发掘了对皮肤干燥症或皮肤屏障的改善、抗过敏及抗炎症尤其优异的肽。
因此，本发明提供一种ZAG蛋白来源肽在制备用于预防、治疗或改善皮肤干燥症或皮肤屏障功能障碍的药物或化妆品中的用途、一种ZAG蛋白来源肽在制备抗过敏药物或化妆品中的用途、以及一种ZAG蛋白来源肽在制备抗炎症药物或化妆品中的用途。
此外，本发明还提供一种用于预防、治疗或改善皮肤干燥症或皮肤屏障功能障碍的、包含上述ZAG蛋白来源肽作为活性成分的药物组合物、一种用于改善皮肤干燥症或皮肤屏障功能障碍的包含上述ZAG蛋白来源肽作为活性成分的化妆品组合物、一种包含上述ZAG蛋白来源肽作为活性成分的抗过敏用药物组合物、一种包含上述ZAG蛋白来源肽作为活性成分的化妆品组合物、一种包含上述ZAG蛋白来源肽作为活性成分的抗炎症用的药物组合物或化妆品组合物。
此外，本发明还提供包括向受试者施用从治疗或生理学上有效剂量的ZAG蛋白来源肽的用于预防、治疗或改善皮肤干燥症或皮肤屏障功能障碍的方法，包括向受试者施用从治疗或生理学上有效剂量的ZAG蛋白来源肽的用于预防、治疗或改善过敏性疾病的方法，包括向受试者施用从治疗或生理学上有效剂量的ZAG蛋白来源肽的用于预防、治疗或改善炎症的方法。
本发明中使用的术语“ZAG蛋白来源肽”是指，在ZAG蛋白的氨基酸序列中显示出改善皮肤干燥症或皮肤屏障功能作用的活性肽。具体地，“ZAG蛋白来源肽”可以为由10-mer以上且50-mer以下的氨基酸序列组成的包含ZAG蛋白的片段的肽。在组成ZAG蛋白的氨基酸序列中，“ZAG蛋白来源肽”中包含的ZAG蛋白的片段可以由10-mer以上且50-mer以下的连续的氨基酸序列组成，例如，可以由10-mer至30-mer、10-mer至25-mer、10-mer至20-mer、10-mer至15-mer的连续的氨基酸序列组成。
在本发明的一个具体例中，ZAG蛋白的片段可以由组成ZAG蛋白的氨基酸序列中的10-mer至30-mer的连续氨基酸序列组成。
在本发明的一个具体例中，ZAG蛋白的片段可以由选自SEQ ID NO：1至SEQ ID NO：19中的任一种氨基酸序列组成。
在本发明的一个具体例中，ZAG蛋白的片段可以由选自SEQ ID NO：20至SEQ IDNO：26中的任一种氨基酸序列组成。
在本发明的说明书中，“ZAG蛋白来源肽”可以与“ZAG蛋白的片段”互换使用。例如，ZAG蛋白来源肽可以由选自SEQ ID NO：1至SEQ ID NO：19中的任一种氨基酸序列组成。此外，ZAG蛋白来源肽可以由选自SEQ ID NO：20至SEQ ID NO：26中的任一种氨基酸序列组成。
在下述实施例中，将公开展示出改善皮肤干燥症、改善皮肤屏障功能、抗过敏或抗炎症效果的ZAG蛋白来源肽。尽管不限于此，本发明的“ZAG蛋白来源肽”可以为表1中所示的Z1至Z18的ZAG蛋白来源肽(分别为SEQ ID NO：1至SEQ ID NO：18)。这些肽已被确认有能够改善皮肤干燥症或皮肤屏障功能、抗过敏和抗炎的作用。尤其可确认，Z3的ZAG蛋白来源肽特应性皮炎具有与ZAG蛋白相同水平地免疫反应降低功效而展示出改善特应性皮炎的效果。在本发明的一个具体例中，“ZAG蛋白来源肽”可以为如表4所示的Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4(分别为SEQ ID NO：20至SEQ ID NO：26)的ZAG蛋白来源肽。
Z1至Z18、或者Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4的肽仅为本发明的“ZAG蛋白来源肽”的示例，“ZAG蛋白来源肽”可以为Z1至Z1、或者Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4中的部分序列。此外，“ZAG蛋白来源肽”可以为各肽中的部分相组合的肽。
根据本发明的“ZAG蛋白来源肽”可以包含，例如，与Z1至Z18的肽，或者与Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4的肽的氨基酸序列分别具有75％或以上、优选为80％或以上、更优选为90％，最优选为95％或以上的序列同源性的氨基酸序列。
此外，除了包含构成活性肽的氨基酸序列，即ZAG蛋白的片段之外，“ZAG蛋白来源肽”还可以包含为实现特定目而制作的氨基酸序列，以增加细胞可渗透肽、靶向序列、标记(tag)、标记的残基、半衰期或肽稳定性。例如，本发明可以在Z1至Z18的肽，或者Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4的肽的任一端融合用于增加细胞可渗透肽、靶向序列、标记、标记的残基、半衰期或肽稳定性的氨基酸序列的融合肽。
此外，根据本发明的“ZAG蛋白来源肽”还可以包含其功能变体。所述功能变体包括本发明中所记载的“ZAG蛋白来源肽”的生物等效物。例如，可以对肽的氨基酸或多核苷酸序列给予进一步改变，以加以改善肽结合亲和力和/或其他生物特性。这样的改变包括抗体的氨基酸序列残基的缺失、插入和/或取代，会根据氨基酸侧链取代基的相对相似性，例如，疏水性、亲水性、电荷大小等进行。通过分析氨基酸侧链取代基的大小、形状和类型，可知精氨酸、赖氨酸和组氨酸均为带正电荷的残基；丙氨酸、甘氨酸和丝氨酸的大小相似；苯丙氨酸、色氨酸和酪氨酸具有相似的形状。因此，基于此，可以说精氨酸、赖氨酸和组氨酸；丙氨酸、甘氨酸和丝氨酸；苯丙氨酸、色氨酸和酪氨酸等是生物学上的功能等同物。
此外，本发明的肽可以通过本领域公知的各种方法获得。例如，可以通过使用多核苷酸重组和蛋白质表达系统来制作，或者通过化学合成如肽合成在试管内的合成、以及通过无细胞蛋白质合成等方法来制作。
此外，为了获得更好的化学稳定性、增强的药理特性(半衰期、吸收性、潜在性、效力等)、改变的特异性(例如，更宽的生物活性谱)、降低的抗原性，肽的N-或C-末端上可以连接保护基。优选地，所述保护基可以是乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂基或聚乙二醇(PEG)，只要是对肽进行改性，特别是能够增强肽的稳定性的成分，则可以不限制。本文所用术语“稳定性”不仅是指保护本发明的肽免受体内蛋白酶攻击的体内稳定性，而且还指储存稳定性(例如，室温储存稳定性)。
本发明的“ZAG蛋白来源肽”的含量，相对于组合物的总重量，可以占所述药物组合物或化妆品组合物的0.0001至50重量％，但不限于此。根据本发明的药物组合物或化妆品组合物除了“ZAG蛋白来源肽”以外，还可包含一种或多种表现出相同或相似功能的活性成分。
同时，本发明的“ZAG蛋白来源肽”可通过药学或生理学上、或化妆品学上可接受的载体，例如胶体悬浮液、粉末、盐水、脂质、脂质体、微球或纳米球形粒子被带入受试者体内。这些可以与运载体形成复合体或与运载体关联，并且通过在本领域中已知的递送系统，例如脂质、脂质体、微粒、金、纳米粒子、聚合物、缩合剂、多糖、聚氨基酸、树状聚合物、皂苷、吸附增强物质或脂肪酸递送至体内。
此外，药学上、生理上或化妆品学上可接受的载体包括但不限于乳糖、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、橡胶、磷酸钙、藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油等。除上述成分外，还可包括润滑剂、湿润剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。
本文所用的术语“皮肤干燥症”是指，由于皮肤缺乏水分导致的皮肤干燥引起的所有症状。本说明书中的上述皮肤干燥症只要是由皮肤中水分不足而导致皮肤干燥引起的症状，对其具体症状的种类和程度没有特别限制。
本文所用术语“皮肤屏障功能”是指，充当外部屏障层的任何功能，例如皮肤的角质层(特别是表皮的角质层)防止水分向外部流出并控制物质从外部进入。另外，本文所用术语“皮肤屏障功能障碍”不仅指皮肤屏障功能恶化或受损的状况，而且指皮肤屏障功能可能降低或受损或需要预防的任何状况。本说明书中的皮肤屏障功能障碍只要是由皮肤屏障功能的恶化或损害引起的症状，则对具体症状的种类或症状的程度没有特别限制。
在本发明的一个具体例中，表现出皮肤干燥症或皮肤屏障功能障碍的疾病可以是特应性皮炎。已经确认，根据本发明的ZAG蛋白来源肽在预防、治疗和改善特应性皮炎方面具有卓越的效果。
进一步，本发明的发明人已经发现，通过用ZAG蛋白处理表皮，可以降低各种免疫反应以及与因此引起的炎性反应有关的Th2细胞，还可以降低各种炎性细胞因子水平和组胺水平。进一步，本发明的发明人已经发现，ZAG蛋白可以增加作为免疫调节细胞的Treg细胞(regulatory T cell)的水平。
其中，炎性细胞因子和Treg细胞可以与过敏性疾病，尤其与特应性特应性皮炎的进展有关。特别地，本发明的发明人发现特应性皮炎患者的血液中Th2细胞分泌的IL-4、IL-5和IL-13的水平以及Th17细胞分泌的IL-17的水平有显著增加。此时，IL-17水平的升高可以为免疫学异常的特征之一。因此，降低炎性细胞因子表达水平的机制，尤其降低Th2和Th17细胞因子水平的机制，可能在抑制炎症反应、预防特应性皮炎，进一步预防和治疗过敏性疾病中起到关键作用。
进一步，与正常人相比,特应性皮炎的病变部位的Treg细胞可能会减少。此时，Treg细胞不仅是作为免疫调节细胞起到作用于Th1、Th2和Th17细胞的树突状细胞的启动作用，而且还能抑制炎症反应并直接影响过敏原特异性Th2细胞的活性，在过敏反应的效应器阶段，可以将必需细胞因子IL-4、IL-5和IL-13的产生减至最少。此外，Treg细胞直接作用于肥大细胞、嗜碱性粒细胞和嗜酸性粒细胞，以抑制过敏炎症并与组织细胞相互作用，能够在组织重构中起重要作用，且直接影响B细胞，以抑制过敏原特异性IgE的产生并诱导IgG4的产生。因此，增强或增加Treg细胞功能的机制在抑制免疫反应或由此引起的炎症反应中是重要的。进一步，该机制在预防和治疗过敏性疾病，特别是特应性皮炎中起到重要作用。
因此，本发明的发明人认识到，可以提供能够调节炎性细胞因子和Treg细胞的水平的ZAG蛋白作为对预防或治疗过敏性疾病有效的抗过敏药物组合物，甚至作为抗炎症药物组合物。
此外，本发明进一步提供一种包含ZAG蛋白来源肽的抗过敏药物或抗过敏化妆品组合物、一种用于预防、治疗或改善过敏性疾病的药物组合物或化妆品组合物以及一种用于抗炎症的药物组合物或化妆品组合物。
根据本发明实施例的抗过敏药物组合物、用于预防或治疗过敏性疾病的药物组合物以及抗炎症组合物可以用作预防或治疗各种过敏性疾病的组合物。例如，上述抗过敏药物组合物可以用于预防或治疗包括过敏反应、过敏性鼻炎、哮喘、特应性皮炎、昆虫过敏、食物过敏、药物过敏和荨麻疹等的过敏性疾病。更优选地，根据本发明实施方式的抗过敏药物组合物可以有效地用作预防或治疗特应性皮炎的组合物，但不限于此。另外，根据本发明实施例的包含ZAG蛋白来源肽的抗炎症药物组合物可以通过降低炎性细胞因子的水平来抑制炎性反应，因此可以有效用于炎症性皮肤疾病，特别是特应性皮炎。
本发明所用术语“预防”是指通过施用包含根据本发明的ZAG蛋白来源肽的药物组合物或化妆品组合物来抑制或延迟“皮肤干燥症”、“皮肤屏障功能障碍”、“过敏性疾病或过敏”或“炎症”的任何行为。
本发明所用术语“治疗”是指通过施用包含根据本发明的ZAG蛋白来源肽的药物组合物或化妆品组合物来使“皮肤干燥症”、“皮肤屏障功能障碍、“过敏性疾病或过敏”或“炎症”好转或对其有利的任何行为。
本发明所用术语“改善”是指通过施用包含根据本发明的ZAG蛋白来源肽的药物组合物或化妆品组合物来缓解“皮肤干燥症”、“皮肤屏障功能障碍”、“过敏性疾病或过敏”或“炎症”的任何行为。
本发明所用术语“受试者”是指需要预防、治疗或改善“皮肤干燥症”、“皮肤屏障功能障碍”、“过敏性疾病或过敏”或“炎症”的受试者，更具体指人类或非人类灵长类、老鼠、狗、猫、马以及牛等哺乳动物。
ZAG蛋白来源肽可经非口服或口服给予受试者。尽管不限于此，但是ZAG蛋白来源肽用于预防、治疗或改善“皮肤干燥”，“皮肤屏障功能障碍”，“过敏性疾病或过敏”或“炎症”的目的，因此可以以非口服，特别是以适用于皮肤的形式配制成药物或化妆品组合物并局部给药。例如，可以将其配制成软膏剂、凝胶剂、膏剂、乳剂等。局部施用的形式可以是但不限于例如施用于皮肤、使用微针的透皮渗透、皮内注射等。例如，可能需要将组合物施用或将包含该组合物的贴剂粘贴到皮肤上。
除了上述用于给药的ZAG蛋白来源肽以外，该组合物还可包含药学或生理学上可接受的载体、赋形剂、稀释剂。可以包含在此类组合物中的合适载体、赋形剂和稀释剂的实例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、无定形纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、茶酸镁、矿物油等。当配制时，该组合物可以进一步包含常规的填充剂、增量剂、粘合剂、崩解剂、表面活性剂、抗凝剂、润滑剂、润湿剂、香料、乳化剂、防腐剂等。
此类组合物的制剂可包括溶液、乳液(包括微乳液)、悬浮液、膏剂、乳剂、凝胶，粉末，或为了适用于可使用该组合物的皮肤或其他组织而使用的其他典型的固体或液体组合物。此类组合物可包含其他抗菌剂、保湿剂和水化剂、渗透剂、防腐剂、乳化剂、天然油或合成油、溶剂、表面活性剂、洗涤剂、胶凝剂、软化剂、抗氧化剂、香料、填充剂、增稠剂、蜡、气味吸收剂、染料、着色剂、粉末、粘度调节剂和水以及可选地包括麻醉剂、止痒活性剂、植物提取物、调理剂、黑化剂或增亮剂、闪光剂、湿润剂、云母、矿物质、多酚，硅酮或其来源物、防晒剂、维生素和药用植物药。
本发明的一个具体例可以提供包含ZAG蛋白来源肽的化妆品组合物，并且具体可以是用于过敏性皮肤改善、抗过敏或消炎的化妆品组合物。化妆品组合物可具有选自悬浮液、乳液、凝胶和糊剂的制剂，但不限于此。
所述组合物的剂量会根据受试者的体重、年龄、性别、健康状况、饮食、给药时间、给药方法、排泄率和疾病严重程度而变化。日剂量为约0.001至100mg/kg，例如0.01至10mg/kg，但不限于此。上述组合物可以一天一次或分几次给药。
本发明提供了一种预防、治疗或改善皮肤干燥或皮肤屏障功能障碍的方法，该方法包括将从治疗上或生理学上有效量的ZAG蛋白来源肽向受试者进行给药。
有益效果
根据本发明的ZAG蛋白肽会对急性、慢性和特应性皮炎具有免疫反应降低功效，而确认具有改善特应性皮炎的效果，通过降低免疫反应、降低IgE的表达，可用于预防、治疗或改善特应性皮炎等的皮肤干燥症、皮肤屏障功能障碍、过敏性疾病、炎症等。
附图说明
图1是每种肽对特应性皮炎效力的体外测试结果。其中，(a)为RAW 264.7巨噬细胞的结果，(b)为RBL-2H3肥大细胞的结果，(c)为角质形成细胞的结果，(d)为B淋巴细胞的结果，(e)为T淋巴细胞的结果。
图2是表4中的每种肽对特应性皮炎效力的体外测试结果。其中，(a)为RAW 264.7巨噬细胞的结果，(b)为RBL-2H3肥大细胞的结果，(c)为角质形成细胞的结果，(d)为B淋巴细胞的结果，(e)为T淋巴细胞的结果。
具体实施方式
参考后述的实施例，便可明确本发明的优点、特征及方法。但是本发明并不局限于以下公开的实施例，可以通过多种形式实现，本实施例只是使本发明更加公开完整，并为了向本发明所属技术领域的人完整地告知本发明的范畴而提供，本发明仅以权利要求的范畴所定义。
【制备例1】肽的合成及分离提纯
为了在298个整个氨基酸序列(GenBank:AAH05306.1)(SEQ ID NO：19)中具有15个重复氨基酸，设定18个肽候选组(Z1～Z18，分别为SEQ ID NO：1～SEQ ID NO：18)，以从ZAG蛋白质中发掘出包含活性部位的肽。各个肽通过固相合成法(solid phase synthesis)制作。通过HPLC分析，本发明所合成的肽达到了90％或以上的纯度。通过质谱法(MassSpectrometry)，确认了纯化肽的分子量(表1：为了确定ZAG蛋白质活性部位而使用的肽候选组及氨基酸序列)。
【表1】
【实施例1】通过体外(In Vitro)特应性皮炎效力实验的肽筛选
为了从18个肽候选组中筛选出能够缓解特应性皮炎症状的ZAG核心活性区域的氨基酸序列，进行特应性皮炎效力实验。ZAG肽候选组(Z1-Z18，分别为SEQ ID NO：1～SEQ IDNO：18)和ZAG蛋白(Z0，SEQ ID NO：19)，以1μg/ml浓度，对5种免疫相关细胞分别处理24小时后，对各细胞株按各时间处理相应的刺激物，并确认免疫反应。对阳性对照实验组仅处理刺激物，而对阴性对照实验组未处理刺激物，但处理溶媒(vehicle)(表2：特应性皮炎效力实验方法)。作为刺激物的炎症反应相关酶由炎症细胞产生，组胺(histamine)可以引发炎症反应。移动到损伤部位的免疫细胞可分泌如肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-6(interleukin-6，IL-6)的细胞因子(cytokine)，可直接破坏外侵物质或聚集其他免疫细胞引起炎症反应。同时，为确认免疫反应，通过利用作为炎症引发物的干扰素-γ(interferon-γ)和皮肤炎症相关因子CCL-17/TARC(胸腺活化调节趋化因子)进行的效力实验。
【表2】
【实施例1-1】利用巨噬细胞(Macrophage)的特应性皮炎效力实验
将巨噬细胞(RAW 264.7细胞)用0.1μg/ml浓度的刺激物(stimulator)LPS处理24小时后，通过ELISA试验确认细胞培养基中释放出的IL-6浓度。在Z0、Z1～Z10、Z14处理实验组中，IL-6浓度比仅处理刺激物(stimulator)的实验组出现显著减少。(图1-a)
【实施例1-2】利用肥大细胞(Mast cell)的特应性皮炎效力实验
将肥大细胞(RBL-2H3)用刺激物PMA(1μg/ml)和A23187(1μg/ml)处理12小时后，通过ELISA试验，确认细胞培养基中释放出的组胺的浓度。Z0、Z1～Z11、Z14、Z15、Z17、Z18处理实验组中，组胺浓度比仅处理刺激物的实验组出现显著减少。(图1-b)
【实施例1-3】利用角质形成细胞(Keratinocyte)的特应性皮炎效力实验
将角质形成细胞(HaCaT cell)用刺激物TNF-α(0.4μg/ml)和IFN-γ(0.4μg/ml)处理24小时后,通过ELISA试验确认细胞培养基中释放出的CCL17/TARC的浓度。Z0、Z1～Z8、Z10、Z12～Z14、Z18处理实验组中，CCL17/TARC出现显著减少。(图1-c)
【实施例1-4】利用B淋巴细胞的特应性皮炎效力实验
将B淋巴细胞(RPMI 1788)用0.1μg/ml浓度的刺激物LPS处理24小时后，通过ELISA试验确认，在细胞培养基中释放出的IgE浓度。Z0、Z3～Z8、Z12～Z1、Z16～Z18处理实验组的IgE出现显著减少。(图1-d)
【实施例1-5】利用T淋巴细胞的特应性皮炎效力实验
根据上述的实施例1-1到1-4的结果判断，通过用6个肽候补组(Z3、Z4、Z5、Z12、Z14、Z15)，进行对T淋巴细胞的特应性皮炎效力实验。将T淋巴细胞用50ng/ml浓度的刺激物IL-2处理12小时后，通过ELISA试验确认，在细胞培养基中释放出的IL-4浓度。此时，经处理的样品组Z3、Z4、Z5、Z12、Z14、Z15中的IL-4出现显著减少。(图1-e)
通过5种细胞株进行的特应性皮炎效力实验，其结果表明，Z3肽在全部细胞株均发挥效力，并确认其为有助于特应性皮炎的物质。(表3)
【表3】ZAG蛋白来源肽的效力实验结果
【制备例2】ZAG来源肽的合成
从Z1到Z18的18个肽候补组中，将筛选出的具有能够缓解特应性皮炎症状之效的ZAG核心活性区域ZAG3肽(ZAG3)作为基础，合成了ZAG3来源寡肽(表4)。表4中各个肽通过固相合成法(solid phase synthesis)进行制备。通过HPLC分析，确认本发明所合成的肽达到了90％或以上的纯度。通过质谱法(Mass Spectrometry)确认经纯化的肽的分子量。
【表4】
【实施例2】通过体外特应性皮炎效力的肽筛选
为了在合成的Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4的肽中筛选出更优秀的氨基酸序列，进行了特应性皮炎效力实验。将Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4，分别以1μg/mL浓度，对各种免疫细胞处理24小时后，将相应刺激物按各个时间段分别处理各个细胞株，并确认免疫反应。特应性皮炎效果的测试按与实施例1和表2相同的方法进行。
按以下进行实验：1)阴性对照组:溶媒(vehicle)处理组(Neg)；2)阳性对照组：仅处理刺激物的组(Pos)；3)实验组：分别处理刺激物和ZAG3或ZAG3来源寡肽(Z20mer-1、Z20mer-2、Z20mer-3、Z15mer-1、Z15mer-2、Z15mer-3、Z15mer-4)的组。通过利用细胞培养液，使用ELISA对浓度进行测定。
【实施例2-1】利用巨噬细胞(Macrophage)的特应性皮炎效力实验
对巨噬细胞(RAW 264.7细胞)用0.1μg/ml浓度的刺激物LPS处理24小时后，通过ELISA试验，确认在细胞培养基中释放的IL-6浓度。与阳性对照组(Pos)相比，在ZAG3、20mer-3、15mer-1、15mer-2、15mer-3、15mer-4处理组中的IL-6浓度有显著减少。(图2-a)
【实施例2-2】利用肥大细胞(Mast cell)的特应性皮炎效力实验
将肥大细胞(RBL-2H3)用刺激物PMA(1μg/ml)和A23187(1μg/ml)处理12小时后，通过ELISA试验，确定在细胞培养基中释放的组胺浓度。与阳性对照组(Pos)相比，在所有寡肽中处理时组胺释放均有减少。(图2-b)
【实施例2-3】利用角质形成细胞的特应性皮炎效力实验
将角质形成细胞(HaCaT细胞)用刺激物TNF-α(0.4μg/ml)和IFN-γ(0.4μg/ml)处理24小时后,通过ELISA试验，确认在细胞培养基中释放的CCL17/TARC的浓度。与阳性对照组(Pos)相比,在ZAG3、20mer-1、15mer-3、15mer-4处理组中的CCL17/TARC浓度出现显著减少。(图2-c)
【实施例2-4】利用B淋巴细胞的特应性皮炎效力实验
将B淋巴细胞(RPMI 1788)用0.1μg/ml浓度的刺激物LPS处理24小时后，通过ELISA试验，确认在细胞培养基中释放的IgE浓度。与阳性对照组(Pos)相比，确认所有寡肽中处理时的IgE均有减少。(图2-d)
【实施例2-5】利用T淋巴细胞的特应性皮炎效力实验
将使用上述实验筛选出的目标肽，对T淋巴细胞进行实验。结果显示，与阳性对照组(Pos)相比较，所有寡肽(Z20mer-1,Z20mer-2,Z20mer-3,Z15mer-1,Z15mer-2,Z15mer-3,Z15mer-4)中处理时的IL-4浓度均有减少。(图2-e)
通过以上5种细胞株的特应性皮炎效力实验，经过总肽(total peptide)的效力比较分析，得出如下结果。与阳性对照组相比，出现统计学上的显著提高，从而判断具有效果，进而确认有助于特应性皮炎。(表5)
【表5】ZAG蛋白来源肽效力实验结果
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<110> 爱恩斯生物有限公司
<120> ZAG来源肽及其用途
<130> X18E10D0181
<150> KR10-2017-0127139
<151> 2017-09-29
<160> 26
<170> PatentIn version 3.2
<210> 1
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 1
Gln Glu Asn Gln Asp Gly Arg Tyr Ser Leu Thr Tyr Ile Tyr Thr Gly
1 5 10 15
Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln Ala Leu
20 25 30
<210> 2
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 2
Gly Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys Asp Arg
1 5 10 15
Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met
20 25 30
<210> 3
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 3
Glu Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile
1 5 10 15
Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp
20 25 30
<210> 4
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 4
Ser Asn Gly Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile Glu
1 5 10 15
Asn Asn Arg Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp
20 25 30
<210> 5
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 5
Gly Lys Asp Tyr Ile Glu Phe Asn Lys Glu Ile Pro Ala Trp Val Pro
1 5 10 15
Phe Asp Pro Ala Ala Gln Ile Thr Lys Gln Lys Trp Glu Ala
20 25 30
<210> 6
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 6
Glu Pro Val Tyr Val Gln Arg Ala Lys Ala Tyr Leu Glu Glu Glu Cys
1 5 10 15
Pro Ala Thr Leu Arg Lys Tyr Leu Lys Tyr Ser Lys Asn Ile
20 25 30
<210> 7
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 7
Leu Asp Arg Gln Asp Pro Pro Ser Val Val Val Thr Ser His Gln Ala
1 5 10 15
Pro Gly Glu Lys Lys Lys Leu Lys Cys Leu Ala Tyr Asp Phe
20 25 30
<210> 8
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 8
Tyr Pro Gly Lys Ile Asp Val His Trp Thr Arg Ala Gly Glu Val Gln
1 5 10 15
Glu Pro Glu Leu Arg Gly Asp Val Leu His Asn Gly Asn Gly
20 25 30
<210> 9
<211> 30
<212> PRT
<213> Homo sapiens
<400> 9
Thr Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro Gln Asp Thr Ala
1 5 10 15
Pro Tyr Ser Cys His Val Gln His Ser Ser Leu Ala Gln Pro
20 25 30
<210> 10
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 10
Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln Ala Leu Gly
1 5 10 15
Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys Asp
20 25 30
<210> 11
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 11
Arg Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met Glu
1 5 10 15
Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp
20 25 30
<210> 12
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 12
Pro Phe Asp Pro Ala Ala Gln Ile Thr Lys Gln Lys Trp Glu Ala Glu
1 5 10 15
Pro Val Tyr Val Gln Arg Ala Lys Ala Tyr Leu Glu Glu Glu
20 25 30
<210> 13
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 13
Cys Pro Ala Thr Leu Arg Lys Tyr Leu Lys Tyr Ser Lys Asn Ile Leu
1 5 10 15
Asp Arg Gln Asp Pro Pro Ser Val Val Val Thr Ser His Gln
20 25 30
<210> 14
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 14
Ile Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser
1 5 10 15
Asn Gly Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile
20 25 30
<210> 15
<211> 30
<212> PRT
<213> Homo sapiens
<400> 15
Glu Asn Asn Arg Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly
1 5 10 15
Lys Asp Tyr Ile Glu Phe Asn Lys Glu Ile Pro Ala Trp Val
20 25 30
<210> 16
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 16
Ala Pro Gly Glu Lys Lys Lys Leu Lys Cys Leu Ala Tyr Asp Phe Tyr
1 5 10 15
Pro Gly Lys Ile Asp Val His Trp Thr Arg Ala Gly Glu Val
20 25 30
<210> 17
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 17
Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His Asn Gly Asn Gly Thr
1 5 10 15
Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro Gln Asp Thr
20 25 30
<210> 18
<211> 30
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 18
Ala Val Pro Pro Gln Asp Thr Ala Pro Tyr Ser Cys His Val Gln His
1 5 10 15
Ser Ser Leu Ala Gln Pro Leu Val Val Pro Trp Glu Ala Ser
20 25 30
<210> 19
<211> 298
<212> PRT
<213> Homo sapiens
<400> 19
Met Val Arg Met Val Pro Val Leu Leu Ser Leu Leu Leu Leu Leu Gly
1 5 10 15
Pro Ala Val Pro Gln Glu Asn Gln Asp Gly Arg Tyr Ser Leu Thr Tyr
20 25 30
Ile Tyr Thr Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln
35 40 45
Ala Leu Gly Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys
50 55 60
Asp Arg Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met
65 70 75 80
Glu Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile
85 90 95
Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser Asn
100 105 110
Gly Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile Glu Asn Asn
115 120 125
Arg Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly Lys Asp Tyr
130 135 140
Ile Glu Phe Asn Lys Glu Ile Pro Ala Trp Val Pro Phe Asp Pro Ala
145 150 155 160
Ala Gln Ile Thr Lys Gln Lys Trp Glu Ala Glu Pro Val Tyr Val Gln
165 170 175
Arg Ala Lys Ala Tyr Leu Glu Glu Glu Cys Pro Ala Thr Leu Arg Lys
180 185 190
Tyr Leu Lys Tyr Ser Lys Asn Ile Leu Asp Arg Gln Asp Pro Pro Ser
195 200 205
Val Val Val Thr Ser His Gln Ala Pro Gly Glu Lys Lys Lys Leu Lys
210 215 220
Cys Leu Ala Tyr Asp Phe Tyr Pro Gly Lys Ile Asp Val His Trp Thr
225 230 235 240
Arg Ala Gly Glu Val Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His
245 250 255
Asn Gly Asn Gly Thr Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro
260 265 270
Gln Asp Thr Ala Pro Tyr Ser Cys His Val Gln His Ser Ser Leu Ala
275 280 285
Gln Pro Leu Val Val Pro Trp Glu Ala Ser
290 295
<210> 20
<211> 20
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 20
Glu Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile
1 5 10 15
Phe Met Glu Thr
20
<210> 21
<211> 20
<212> PRT
<213> artificial
<220>
<223> ZAG protein-derived peptide
<400> 21
Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile Phe Met Glu Thr Leu
1 5 10 15
Lys Asp Ile Val
20
<210> 22
<211> 20
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 22
Lys Ala Arg Glu Asp Ile Phe Met Glu Thr Leu Lys Asp Ile Val Glu
1 5 10 15
Tyr Tyr Asn Asp
20
<210> 23
<211> 15
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 23
Glu Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp
1 5 10 15
<210> 24
<211> 15
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 24
Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile Phe Met Glu Thr
1 5 10 15
<210> 25
<211> 15
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 25
Lys Ala Arg Glu Asp Ile Phe Met Glu Thr Leu Lys Asp Ile Val
1 5 10 15
<210> 26
<211> 15
<212> PRT
<213> Artificial
<220>
<223> ZAG protein-derived peptide
<400> 26
Ile Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp
1 5 10 15
Claims (4)
1.锌-α糖蛋白（ZAG）蛋白来源肽在制备用于预防、治疗或改善特应性皮炎的药物中的用途，其中所述ZAG蛋白来源肽的氨基酸序列如选自SEQ ID NO：1至18和20至26中任意一种所示。
2.根据权利要求1所述的用途，其特征在于，所述ZAG蛋白来源肽的氨基酸序列如选自SEQ ID NO：3、21、22和25中任意一种所示。
3.锌-α糖蛋白（ZAG）蛋白来源肽在制备用于预防、治疗或改善特应性皮炎的化妆品组合物中的用途，其中所述ZAG蛋白来源肽的氨基酸序列如选自SEQ ID NO：1至18和20至26中任意一种所示。
4.根据权利要求3所述的用途，其特征在于，所述ZAG蛋白来源肽的氨基酸序列如选自SEQ ID NO：3、21、22和25中任意一种所示。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2017-0127139 | 2017-09-29 | ||
| KR20170127139 | 2017-09-29 | ||
| PCT/KR2018/011593 WO2019066590A1 (ko) | 2017-09-29 | 2018-09-28 | Zag 유래 펩타이드 및 그의 용도 |
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| Publication Number | Publication Date |
|---|---|
| CN111201029A CN111201029A (zh) | 2020-05-26 |
| CN111201029B true CN111201029B (zh) | 2023-10-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201880063919.1A Active CN111201029B (zh) | 2017-09-29 | 2018-09-28 | Zag来源肽及其用途 |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US11213567B2 (zh) |
| KR (1) | KR102149202B1 (zh) |
| CN (1) | CN111201029B (zh) |
| WO (1) | WO2019066590A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022234868A1 (ko) * | 2021-05-03 | 2022-11-10 | 주식회사 엘앤씨바이오 | Zag 유래 펩타이드를 포함하는 흉터 및 켈로이드 개선용 조성물 |
| KR102610535B1 (ko) * | 2021-05-03 | 2023-12-06 | 주식회사 엘앤씨바이오 | Zag 유래 펩타이드를 포함하는 흉터 및 켈로이드 개선용 조성물 |
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| CN1661110A (zh) * | 2003-12-22 | 2005-08-31 | 霍夫曼-拉罗奇有限公司 | 来自脂肪组织的肥胖症新靶 |
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| CN103068400A (zh) * | 2010-06-25 | 2013-04-24 | 阿斯顿大学 | 具有脂类动员性质的糖蛋白及其治疗用途 |
| KR20170026710A (ko) * | 2015-08-26 | 2017-03-09 | 연세대학교 산학협력단 | 알레르기 행진에 대한 신규 바이오마커 및 그의 용도 |
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- 2018-09-28 CN CN201880063919.1A patent/CN111201029B/zh active Active
- 2018-09-28 KR KR1020180116510A patent/KR102149202B1/ko active IP Right Grant
- 2018-09-28 WO PCT/KR2018/011593 patent/WO2019066590A1/ko active Application Filing
- 2018-09-28 US US16/652,045 patent/US11213567B2/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| KR20190038447A (ko) | 2019-04-08 |
| US20200246428A1 (en) | 2020-08-06 |
| WO2019066590A1 (ko) | 2019-04-04 |
| CN111201029A (zh) | 2020-05-26 |
| US11213567B2 (en) | 2022-01-04 |
| KR102149202B1 (ko) | 2020-08-28 |
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