CN108348544A - 用于抑制血管生成的含有纳米颗粒-玻璃体基蛋白质复合物作为活性成分的组合物及其用途 - Google Patents

用于抑制血管生成的含有纳米颗粒-玻璃体基蛋白质复合物作为活性成分的组合物及其用途 Download PDF

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CN108348544A
CN108348544A CN201680052488.XA CN201680052488A CN108348544A CN 108348544 A CN108348544 A CN 108348544A CN 201680052488 A CN201680052488 A CN 201680052488A CN 108348544 A CN108348544 A CN 108348544A
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金正勋
曹东铉
李泰杰
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KOREA STANDARD SCIENCE ACADEMY
Korea Research Institute of Standards and Science KRISS
Seoul National University Industry Foundation
SNU R&DB Foundation
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Abstract

本发明涉及纳米颗粒‑玻璃体基蛋白质复合物，并且更具体地涉及用于抑制血管生成的组合物，所述组合物包含所述复合物作为活性成分，以及涉及用于预防或治疗血管生成相关疾病或视网膜疾病的组合物。根据本发明的纳米颗粒‑玻璃体基蛋白质复合物通过以玻璃体内局部注射，显示与血管内皮生长因子的显著优异结合强度，从而可以抑制血管生成，因此该复合物可以易于用于制备用于预防、减轻或治疗与视网膜和脉络膜血管生成相关的疾病的治疗剂。

Description

用于抑制血管生成的含有纳米颗粒-玻璃体基蛋白质复合物 作为活性成分的组合物及其用途
技术领域
本发明涉及纳米颗粒-玻璃体基蛋白质复合物，并且更具体地涉及用于抑制血管生成的组合物，所述组合物包含所述复合物作为活性成分，以及涉及用于预防或治疗血管生成相关疾病或视网膜疾病的组合物。
背景技术
血管生成是一种为组织或器官提供新血管的生物学过程，尤其是指从现有微血管中生长新的毛细血管，并且是生长后在体内形成血管的基本过程。血管生成过程非常复杂和精细，简要描述如下。首先，当用于血管生成的刺激被传递到现有血管时，血管扩张并且其膜通透性增加。其次，纤维蛋白被释放到扩张的血管的外部以沉积在血管周围的细胞质基质中。第三，用于降解现有血管的基底膜的酶被激活，基底膜被破坏，并且内皮细胞通过被破坏的基底膜从血管释放并且在相邻细胞的基质中增殖并迁移。最后，连续排列的内皮细胞形成血管，从而完成血管生成。
血管生成过程受到各种负调节物和正调节物的严格调控。当血管生成异常调节时，会发生各种疾病，如癌症、类风湿性关节炎、糖尿病视网膜病变等。特别是，在视网膜内发生这种病理性血管生成的情况下，血管生成引起视网膜水肿，视网膜或玻璃体出血和视网膜脱离。此外，视网膜中的血管生成成为早产儿视网膜病变、糖尿病视网膜病变和老年黄斑变性的主要原因。
同时，纳米颗粒(NP)已被广泛用于工业和生物医学目的。特别是，纳米颗粒已被用作生物医学领域如药物递送、基因递送、细胞内成像和光疗中的有前景的材料，并且特别地，由于易于合成和作用、化学稳定性、生物相容性以及其可调节的光学和电学性质，金或二氧化硅纳米材料已经引起了关注。
近来，已知金或银NPs抑制血管内皮生长因子(VEGF)诱导的血管生成，并且已经进行了关于使用其开发血管生成抑制剂的研究。然而，为了使用NPs进行治疗，需要仔细评估NPs的毒性和努力降低毒性。
发明内容
【技术问题】
鉴于上述问题而作出了本发明，并且作为研究并致力于开发对器官特异性抑制视网膜和脉络膜血管生成具有良好作用并显示出低毒性的纳米颗粒治疗剂的结果，发明人验证了纳米颗粒-玻璃体基蛋白质复合物显示出与血管内皮生长因子的显著优异的结合强度，从而基于该发现完成了本发明。
因此，本发明的一个目的是提供一种用于抑制血管生成的药物组合物，其包含由纳米颗粒和围绕纳米颗粒表面的玻璃体基蛋白组成的复合物作为活性成分。
此外，本发明的另一目的在于提供一种用于预防或治疗视网膜疾病的组合物，其包含由纳米颗粒和围绕纳米颗粒表面的玻璃体基蛋白质组成的复合物作为活性成分。
然而，本发明要实现的技术问题不限于上述技术问题，并且从以下描述中本领域普通技术人员将会明白其他未提及的技术问题。
【技术解决方案】
本发明提供用于抑制血管生成的药物组合物，其包含由纳米颗粒和围绕纳米颗粒表面的玻璃体基蛋白组成的复合物作为活性成分。
在本发明的一个实施方案中，纳米颗粒可以是金或二氧化硅。
在本发明的另一个实施方案中，纳米颗粒可以具有20nm至100nm的直径。
在本发明的另一个实施方案中，血管生成可能参与早产儿视网膜病、增殖性视网膜病、年龄相关性黄斑变性、糖尿病性黄斑水肿(DME)、糖尿病视网膜病变或中心性浆液性(脉络膜)视网膜病。
在本发明的另一个实施方案中，玻璃体基蛋白可以是选自由维奇因(vitrin)、分泌型卷曲蛋白相关蛋白2、血清白蛋白、视黄醇结合蛋白3和α-晶状体蛋白A链组成的组中的一种或多种。
本发明提供用于预防或治疗视网膜疾病的药物组合物，其包含所述组合物作为活性成分。
在本发明的一个实施方案中，视网膜疾病可以选自早产儿视网膜病、糖尿病性黄斑水肿(DME)、糖尿病视网膜病变、中心性浆液性(脉络膜)视网膜病、年龄相关性黄斑变性和增殖性视网膜病。
本发明提供筛选适用于治疗视网膜疾病的蛋白质的方法，所述方法包括以下过程：
(1)将纳米颗粒体外注入玻璃体中；
(2)分离玻璃体中的所述纳米颗粒和蛋白质的复合物；
(3)将所述复合物与血管内皮生长因子(VEGF)结合；和
(4)选择与所述VEGF结合的复合物。
本发明提供了抑制血管生成的方法，包括将药学有效量的药物组合物投予个体。
本发明提供预防或治疗视网膜疾病的方法，包括将药学有效量的药物组合物投予个体。
本发明提供了该药物组合物用于抑制血管生成的用途。
本发明提供了该药物组合物用于预防或治疗视网膜疾病的用途。
【有益效果】
当将根据本发明的基于纳米颗粒-玻璃体的蛋白质复合物局部注射到玻璃体腔中时，该复合物显示出与血管内皮生长因子显著优异的结合强度，从而抑制血管生成，因此可以容易地用于制备用于预防、减轻或治疗视网膜和脉络膜血管生成相关疾病的治疗剂。
附图说明
图1示出了直径为20nm或100nm的金和二氧化硅纳米颗粒的透射电子显微镜(TEM)图像。
图2示出了与直径为20nm的金纳米颗粒(Au20)形成冠状物(corona)的前20种基于玻璃体的蛋白质。
图3示出了与直径为20nm的二氧化硅纳米颗粒(Si20)形成冠状物的前20个基于玻璃体的蛋白质。
图4示出了与具有100nm直径的金纳米颗粒(Au100)形成冠状物的前20个基于玻璃体的蛋白质。
图5示出了与直径为100nm的二氧化硅纳米颗粒(Si100)形成冠状物的前20个基于玻璃体的蛋白质。
图6示出了作为图2至5的组合结果，与纳米颗粒形成冠状物的前20个基于玻璃体的蛋白质。
图7示出了用于比较纳米颗粒和纳米颗粒-玻璃体基蛋白质复合物与在水中的血管内皮生长因子的结合强度的实验的示意性过程。
图8示出了用于比较纳米颗粒和纳米颗粒-玻璃体基蛋白质复合物与在玻璃体中的血管内皮生长因子的结合强度的实验的示意性过程。
图9是显示比较纳米颗粒和纳米颗粒-玻璃体基蛋白质复合物与水中和玻璃体内的血管内皮生长因子的结合强度的结果的图。
图10示出了在体外纳米颗粒-玻璃体基蛋白质复合物的体内血管生成抑制作用的验证结果。
图11示出了体内纳米颗粒-玻璃体基蛋白质复合物的血管生成抑制作用的验证结果。
具体实施方式
作为研究并致力开发能够调节视网膜和脉络膜血管生成的方法的结果，本发明的发明人证实，当通过注射器将纳米颗粒局部注射到玻璃体腔中时，纳米颗粒与玻璃体基蛋白形成冠状物，并且这种纳米颗粒-玻璃体基蛋白质复合物显示出与血管内皮生长因子显著优异的结合强度，从而基于该发现完成了本发明。
在下文中，将详细描述本发明。
本发明提供了用于抑制血管生成的药物组合物，其包含由纳米颗粒和围绕纳米颗粒表面的玻璃体基蛋白组成的复合物作为活性成分。
本文使用的术语“血管生成”是指其中血管新形成，即在细胞、组织或器官中形成新血管的过程，并且本文所用的术语“新血管”是指通过血管生成新形成的血管。在本发明中，术语“血管生成”和“新血管”可以互换描述。
此外，在本发明中，血管生成可能参与早产儿视网膜病，增殖性视网膜病，年龄相关性黄斑变性，糖尿病性黄斑水肿(DME)，糖尿病视网膜病变，中心性浆液性(脉络膜)视网膜病或慢性炎症，但本发明不限于此，并且血管生成可能参与由血管生成发生或发展的任意疾病。
本文使用的术语“纳米颗粒”是指具有纳米尺寸直径的各种材料的颗粒，并且纳米颗粒不受特别限制，只要它们是纳米尺寸颗粒即可。然而，当纳米颗粒的直径大于100nm或更大时，纳米颗粒的性质可能消失，因此纳米颗粒可具有20nm至100nm的直径。另外，纳米颗粒可以是金纳米颗粒或二氧化硅纳米颗粒，但是本发明不限于此。
本文使用的术语“玻璃体基蛋白质”是指能够通过与纳米颗粒结合而形成复合物的玻璃体中的蛋白质，并且玻璃体基蛋白质的例子包括但不限于：vitrin，分泌型卷曲相关蛋白2，血清白蛋白，视黄醇结合蛋白3，α-晶状体蛋白A链，β-晶状体蛋白S，β-晶状体蛋白B2，潜伏转化生长因子β-结合蛋白2，补体C4-A，α-烯醇化酶，β-晶状体蛋白B1，脊椎蛋白-1，钙同线蛋白-1，凝溶胶蛋白，视黄醛脱氢酶1，β-晶状体蛋白A2，胶原蛋白α-1(II)链，细胞质肌动蛋白1(actin,cytoplasmic 1)，含有EGF的腓骨蛋白(fibulin)样细胞外基质蛋白1和旋光蛋白(opticin)。优选地，基于玻璃体的蛋白质可以包括选自由vitrin、分泌型卷曲蛋白相关蛋白2、血清白蛋白、视黄醇结合蛋白3和α-晶状体蛋白A链组成的组中的一种或多种蛋白质。同时，vitrin、分泌型卷曲蛋白相关蛋白2、血清白蛋白、视黄醇结合蛋白3和α-晶状体蛋白A链可以分别由SEQ ID NO：1至5的氨基酸序列组成，但是本发明不限于此，可以包括与上述相应的氨基酸序列具有至少70％同源性、优选至少80％同源性、更优选至少90％和最优选至少95％同源性的氨基酸序列。
包含在本发明组合物中作为活性成分的纳米颗粒-玻璃体基蛋白质复合物显示出与血管内皮生长因子的优异的结合强度，因此可以有效地抑制血管生成。
根据本发明的一个实施方案，鉴定了与纳米颗粒结合的前五种基于玻璃体的蛋白质(参见实施例1)，将这前五种蛋白质和纳米颗粒孵育以形成纳米颗粒-玻璃体基蛋白质复合物(见实施例2)，然后作为验证其血管生成抑制作用的结果，证实了所述复合物与在水中的血管内皮生长因子的结合强度与纳米颗粒的情况相比几乎没有差异，而与仅纳米颗粒治疗组相比，所述复合物与玻璃体内的血管内皮生长因子的结合强度显著优异(参见实施例3)。
在本发明的另一实施方式中，作为验证纳米颗粒-玻璃体基蛋白质复合物在体外或体内的血管生成抑制作用的结果，证实了纳米颗粒-玻璃体基蛋白质复合物表现出优异的血管生成体外和体内抑制作用(见实施例4)。
从这些实验结果可以看出，根据本发明的纳米颗粒-玻璃体基蛋白质复合物抑制血管生成，因此可以有效地用于预防、缓解或治疗血管生成相关疾病，特别是视网膜和脉络膜血管生成相关疾病。
因此，本发明的另一个实施方式提供用于预防或治疗血管生成相关疾病的药物组合物，其包含由纳米颗粒和围绕纳米颗粒表面的玻璃体基蛋白组成的复合物作为活性成分。
此外，本发明的另一实施方式提供了一种用于预防或治疗视网膜疾病的药物组合物，其包含由纳米颗粒和围绕纳米颗粒表面的玻璃体基蛋白质组成的复合物作为活性成分。
本文使用的术语“预防”是指通过施用根据本发明的药物组合物来抑制血管生成相关疾病或视网膜疾病或延迟其发作的所有作用。
本文使用的术语“治疗”是指通过施用根据本发明的药物组合物缓解或有益地改变由于血管生成相关疾病或视网膜疾病引起的症状的所有作用。
如本文所用的术语“血管生成相关疾病”是指由于上述血管生成的异常进展而发生的疾病，其实例包括但不限于早产儿视网膜病、增殖性视网膜病、年龄相关性黄斑变性、糖尿病视网膜病变和中心性浆液性(脉络膜)视网膜病变。
本文中使用的术语“视网膜疾病”是指发生的导致在视网膜中发生病变的疾病，其实例包括但不限于早产儿视网膜病、糖尿病性黄斑水肿(DME)、糖尿病视网膜病变、中心性浆液性(脉络膜)视网膜病变、年龄相关性黄斑变性和增殖性视网膜病变。
根据本发明的药物组合物以药学有效量施用。如本文所用的术语“药学有效量”是指足以以适用于医学治疗的合理利益/风险比治疗疾病的量，并且有效剂量水平可以根据包括患者疾病类型、疾病严重程度、药物活性、对药物的敏感性、给药时间、给药途径、排泄率、治疗期、同时使用的药物以及医学领域中众所周知的其他因素的因素来确定。根据本发明的药物组合物可以作为单独的治疗剂施用或与其他治疗剂组合施用，可以与现有的治疗剂相继地或同时施用，并且可以以单剂量或多剂量施用。考虑到所有上述因素，以能够实现最大效果而没有副作用的最小量施用药物组合物是重要的，并且这可以容易地由本领域普通技术人员确定。
根据本发明的药物组合物可以在临床给药时配制成各种口服或肠胃外剂型，可以优选通过玻璃体内注射方法施用，并且可以制备成适于注射到玻璃体腔内的药物制剂。
本发明的另一个实施方案提供了治疗血管生成相关疾病或视网膜疾病的方法，其包括将由纳米颗粒和围绕纳米颗粒表面的基于玻璃体的蛋白质组成的复合物施用给个体。
如本文所用的术语“个体”是指患有需要治疗的疾病的受试者，并且更具体地包括哺乳动物如人或非人灵长类，例如小鼠，大鼠，狗，猫，马，牛等。
本发明的另一个实施方案提供了筛选适用于治疗视网膜疾病的蛋白质的方法，包括以下过程：
(1)将纳米颗粒体外注入玻璃体中；
(2)分离玻璃体中的所述纳米颗粒和蛋白质的复合物；
(3)将所述复合物与血管内皮生长因子(VEGF)结合；和
(4)选择与所述VEGF结合的复合物。
在下文中，将描述示例性实施例以帮助理解本发明。然而，提供以下实施例是为了更容易理解本发明，而不是为了限制本发明的范围。
[实施例]
实施例1.验证基于玻璃体的蛋白质与纳米颗粒的结合
1-1.纳米颗粒的制备
作为与玻璃体基蛋白质结合的纳米颗粒，制备了直径为20nm的金和二氧化硅纳米颗粒以及直径为100nm的金和二氧化硅纳米颗粒。纳米颗粒的具体信息和TEM图像示于表1和图1中。
<表1>
1-2.纳米颗粒与玻璃体基蛋白质结合
通过实施例1-1制备直径为20nm的金(Au 20)和二氧化硅(Si20)纳米颗粒(1×1011)和直径为100nm的金(Au 100)和二氧化硅(Si100)纳米颗粒(1×1011)，将含有170μg蛋白质的所述玻璃体在微量离心管中在4℃下孵育6小时，同时以20rpm旋转。随后，将所得产物以15,000rpm离心20分钟以获得沉淀物，然后用蒸馏水洗涤两次以去除非特异性结合的蛋白质。此时，沉淀物包括游离的纳米颗粒和蛋白质结合的纳米颗粒。将沉淀物悬浮在30μLLaemmli缓冲液中，并在100℃加热3分钟以诱导纳米颗粒和蛋白质的分离。之后，将分离的产物以15,000rpm离心1分钟以获得上清液，使用上清液进行蛋白质分析，并鉴定与相应的纳米颗粒形成冠状物(corona)的前20种基于玻璃体的蛋白质，并且其结果显示在图2至5中。另外，通过将上述结果全部组合在一起来鉴定前20种基于玻璃体的蛋白质，并且其结果显示在图6中。
如图6所示，确认了与纳米颗粒形成冠状物的前5种玻璃体基蛋白依次为vitrin、分泌型卷曲相关蛋白2、血清白蛋白、视黄醇结合蛋白3和α-晶状体蛋白A链，其相对数量分别为11.25％、6.80％、5.44％、4.85％和4.23％。
实施例2.纳米颗粒-玻璃体基蛋白质复合物的形成
制备由通过实施例1-2鉴定的分别具有50ng、25ng、25ng、25ng和25ng重量的前5种基于玻璃体的蛋白质组成的总共150ng蛋白质(SALVAR复合物)，并且将总计150ng的蛋白质和1×109纳米颗粒在4℃下孵育1小时，同时以20rpm旋转以形成纳米颗粒-玻璃体基蛋白质复合物。
实施例3.验证纳米颗粒-玻璃体基蛋白复合物的血管生成抑制作用
已知金和二氧化硅纳米颗粒与在水中或细胞培养物中的血管内皮生长因子结合。因此，为了验证与这些纳米微粒相比，本发明的纳米颗粒-玻璃体基蛋白质复合物是否有效地与在水中或细胞培养物中的血管内皮生长因子结合，如下进行实验。
3-1.与在水中血管内皮生长因子的结合强度的比较
将纳米颗粒与在水中的血管内皮生长因子结合的情况与将纳米颗粒-玻璃体基蛋白质复合物与在水中的血管内皮生长因子的结合的情况进行比较，并且相应实验的示意性过程在图7中示出。
即，将纳米颗粒或纳米颗粒-玻璃体基蛋白质复合物和血管内皮生长因子在4℃、同时以20rpm旋转下孵育6小时。孵育后，将所得产物以15,000rpm离心20分钟以沉淀与纳米颗粒或纳米颗粒-玻璃体基蛋白质复合物结合的血管内皮生长因子，并且通过酶联免疫吸附测定法测定上清液中的游离血管内皮生长因子以确定与血管内皮生长因子的结合强度。
结果，如图9所示，确认了在将纳米颗粒与在水中的血管内皮生长因子结合的实例(“空白(Bare)”组)与将纳米颗粒-玻璃体基蛋白质复合物与血管内皮生长因子结合的实例(“救援(SALVAR)”组)之间的与血管内皮生长因子的结合强度几乎没有差异。
3-2.玻璃体内与血管内皮生长因子的结合强度的比较
将纳米颗粒与玻璃体内的血管内皮生长因子结合的实例与将纳米颗粒-玻璃体基蛋白质复合物与玻璃体内的血管内皮生长因子结合的实例进行比较，并且相应实验的示意性过程是如图8所示。
使用与实施例3-1中使用的方法相同的方法进行实验，不同之处在于使用玻璃体代替水。
结果，如图9所示，确认了与将纳米颗粒与玻璃体中的血管内皮生长因子结合的实例(“玻璃体”组)相比，将纳米颗粒-玻璃体基蛋白质复合物与玻璃体中的血管内皮生长因子结合的实例(“救援(SALVAR)+玻璃体”组)显示出与血管内皮生长因子显著优异的结合强度。
从以上结果可以看出，本发明的纳米颗粒-玻璃体基蛋白质复合物表现出优异的体内治疗效果。
实施例4.体外验证纳米颗粒-玻璃体基蛋白质复合物的体内血管生成抑制作用
已知当用20ng/mL的血管内皮生长因子处理血管内皮细胞时，促进了代表血管生成过程的血管内皮细胞的增殖或管形成。为了验证纳米颗粒-玻璃体基蛋白质复合物的施用是否抑制其中涉及血管内皮生长因子的体外血管生成过程，进行血管内皮细胞增殖和管形成的测试。进行血管内皮细胞增殖试验，使得在0.3％明胶包被板的多个孔的每一个孔中培养2,000个血管内皮细胞1天，然后根据条件用血管内皮生长因子、纳米颗粒、纳米颗粒-玻璃体基蛋白质复合物和贝伐单抗处理，并且将与48小时的血管内皮细胞增殖程度相互比较。使用台盼蓝染色后直接测定细胞数的方法和水溶性四唑盐-1处理后的450nm吸光度的测定方法，估计血管内皮细胞的增殖程度。进行试管形成试验，使得根据条件用血管内皮生长因子、纳米颗粒、纳米颗粒-玻璃体基蛋白质复合物和贝伐单抗处理在基质胶(Matrigel)包被板的多个孔中的每一个孔中的100,000个血管内皮细胞，并在12小时后将血管内皮细胞的管形成程度相互比较。通过检查50倍放大倍数屏幕上的形成的管的数量进行定量比较。
结果，如图10所示，证实了其中施用纳米颗粒-玻璃体基蛋白质复合物(“救援(SALVAR)混合物”)的实例显示了优异的血管生成抑制效果，其相当于贝伐单抗在体外血管内皮细胞增殖和管形成实验中的血管生成抑制效果。
实施例5.体内验证纳米颗粒-玻璃体基蛋白复合物的血管生成抑制作用
在小鼠中产生激光诱导的脉络膜新血管形成模型，并将纳米颗粒或纳米颗粒-玻璃体基蛋白质复合物注射到玻璃体中以测定其作用。用400mW强度的二极管激光器照射小鼠的视网膜持续50ms，以引起视网膜和脉络膜层之间的布鲁赫膜破坏。在激光照射后，将纳米颗粒(109/mL，1μL)、纳米颗粒-玻璃体基蛋白质复合物(109/mL，1μL)和抗血管内皮生长因子抗体(1μg)中的每一种注射入玻璃体，通过免疫荧光染色法验证激光照射后第7天的玻璃体脉络膜新血管生成程度。
结果，如图11所示，证实了其中施用纳米颗粒-玻璃体基蛋白质复合物(“Au20+救援混合物”)的实例显示出优异的血管生成抑制作用，其相当于抗血管内皮生长因子抗体的(甚至其在体内的)作用。
提供本发明的上述描述仅仅是为了说明的目的，并且本发明所属领域的普通技术人员将会理解，本发明可以容易地以其他特定形式进行修改而不改变本发明的技术精神或必要特征。因此，本文描述的实施方案应该被解释为仅用于说明的目的而不是为了限制的目的。
【工业实用性】
当将根据本发明的纳米颗粒-玻璃体基蛋白质复合物局部注射到玻璃体中时，所述复合物显示出与血管内皮生长因子显著优异的结合强度，因此可以抑制血管生成，因此可以用于涉及视网膜和脉络膜血管生成相关疾病的制药工业领域。
序列表自由文字
<110>首尔大学校产学协力团
韩国标准科学研究院
<120>用于抑制血管生成的含有作为活性成分的基于玻璃体的纳米颗粒-蛋白复合物的组合物及其用途
<130>MPCT16-054
<150>KR 10-2015-0099308
<151>2015-07-13
<160>5
<170>KoPatentIn 3.0
<210>1
<211>678
<212>PRT
<213>Vitrin
<400>1
Met Arg Thr Val Val Leu Thr Met Lys Ala Ser Val Ile Glu Met Phe
1 5 10 15
Leu Val Leu Leu Val Thr Gly Val His Ser Asn Lys Glu Thr Ala Lys
20 25 30
Lys Ile Lys Arg Pro Lys Phe Thr Val Pro Gln Ile Asn Cys Asp Val
35 40 45
Lys Ala Gly Lys Ile Ile Asp Pro Glu Phe Ile Val Lys Cys Pro Ala
50 55 60
Gly Cys Gln Asp Pro Lys Tyr His Val Tyr Gly Thr Asp Val Tyr Ala
65 70 75 80
Ser Tyr Ser Ser Val Cys Gly Ala Ala Val His Ser Gly Val Leu Asp
85 90 95
Asn Ser Gly Gly Lys Ile Leu Val Arg Lys Val Ala Gly Gln Ser Gly
100 105 110
Tyr Lys Gly Ser Tyr Ser Asn Gly Val Gln Ser Leu Ser Leu Pro Arg
115 120 125
Trp Arg Glu Ser Phe Ile Val Leu Glu Ser Lys Pro Lys Lys Gly Val
130 135 140
Thr Tyr Pro Ser Ala Leu Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala
145 150 155 160
Gln Ala Gly Glu Thr Thr Lys Ala Tyr Gln Arg Pro Pro Ile Pro Gly
165 170 175
Thr Thr Ala Gln Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val
180 185 190
Ala Val Ala Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro Ser Ala Ala
195 200 205
Ser Thr Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser Gln
210 215 220
Glu Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln Asn Arg
225 230 235 240
Pro Arg Ala Asp Pro Gly Ile Gln Arg Gln Asp Pro Ser Gly Ala Ala
245 250 255
Phe Gln Lys Pro Val Gly Ala Asp Val Ser Leu Gly Leu Val Pro Lys
260 265 270
Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val Ser Leu Gly Asp Pro
275 280 285
Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile
290 295 300
Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala
305 310 315 320
Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln
325 330 335
Tyr Gly Asp Asn Pro Ala Thr His Phe Asn Leu Lys Thr His Thr Asn
340 345 350
Ser Arg Asp Leu Lys Thr Ala Ile Glu Lys Ile Thr Gln Arg Gly Gly
355 360 365
Leu Ser Asn Val Gly Arg Ala Ile Ser Phe Val Thr Lys Asn Phe Phe
370 375 380
Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val
385 390 395 400
Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu
405 410 415
Ala Arg Glu Ser Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala
420 425 430
Ala Glu Asn Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys
435 440 445
Ala Val Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser Trp
450 455 460
Phe Gly Leu His Lys Thr Leu Gln Pro Leu Val Lys Arg Val Cys Asp
465 470 475 480
Thr Asp Arg Leu Ala Cys Ser Lys Thr Cys Leu Asn Ser Ala Asp Ile
485 490 495
Gly Phe Val Ile Asp Gly Ser Ser Ser Val Gly Thr Gly Asn Phe Arg
500 505 510
Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys Glu Phe Glu Ile Ser
515 520 525
Asp Thr Asp Thr Arg Ile Gly Ala Val Gln Tyr Thr Tyr Glu Gln Arg
530 535 540
Leu Glu Phe Gly Phe Asp Lys Tyr Ser Ser Lys Pro Asp Ile Leu Asn
545 550 555 560
Ala Ile Lys Arg Val Gly Tyr Trp Ser Gly Gly Thr Ser Thr Gly Ala
565 570 575
Ala Ile Asn Phe Ala Leu Glu Gln Leu Phe Lys Lys Ser Lys Pro Asn
580 585 590
Lys Arg Lys Leu Met Ile Leu Ile Thr Asp Gly Arg Ser Tyr Asp Asp
595 600 605
Val Arg Ile Pro Ala Met Ala Ala His Leu Lys Gly Val Ile Thr Tyr
610 615 620
Ala Ile Gly Val Ala Trp Ala Ala Gln Glu Glu Leu Glu Val Ile Ala
625 630 635 640
Thr His Pro Ala Arg Asp His Ser Phe Phe Val Asp Glu Phe Asp Asn
645 650 655
Leu His Gln Tyr Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe
660 665 670
Asn Ser Gln Pro Arg Asn
675
<210>2
<211>295
<212>PRT
<213>分泌型卷曲相关蛋白2
<400>2
Met Leu Gln Gly Pro Gly Ser Leu Leu Leu Leu Phe Leu Ala Ser His
1 5 10 15
Cys Cys Leu Gly Ser Ala Arg Gly Leu Phe Leu Phe Gly Gln Pro Asp
20 25 30
Phe Ser Tyr Lys Arg Ser Asn Cys Lys Pro Ile Pro Ala Asn Leu Gln
35 40 45
Leu Cys His Gly Ile Glu Tyr Gln Asn Met Arg Leu Pro Asn Leu Leu
50 55 60
Gly His Glu Thr Met Lys Glu Val Leu Glu Gln Ala Gly Ala Trp Ile
65 70 75 80
Pro Leu Val Met Lys Gln Cys His Pro Asp Thr Lys Lys Phe Leu Cys
85 90 95
Ser Leu Phe Ala Pro Val Cys Leu Asp Asp Leu Asp Glu Thr Ile Gln
100 105 110
Pro Cys His Ser Leu Cys Val Gln Val Lys Asp Arg Cys Ala Pro Val
115 120 125
Met Ser Ala Phe Gly Phe Pro Trp Pro Asp Met Leu Glu Cys Asp Arg
130 135 140
Phe Pro Gln Asp Asn Asp Leu Cys Ile Pro Leu Ala Ser Ser Asp His
145 150 155 160
Leu Leu Pro Ala Thr Glu Glu Ala Pro Lys Val Cys Glu Ala Cys Lys
165 170 175
Asn Lys Asn Asp Asp Asp Asn Asp Ile Met Glu Thr Leu Cys Lys Asn
180 185 190
Asp Phe Ala Leu Lys Ile Lys Val Lys Glu Ile Thr Tyr Ile Asn Arg
195 200 205
Asp Thr Lys Ile Ile Leu Glu Thr Lys Ser Lys Thr Ile Tyr Lys Leu
210 215 220
Asn Gly Val Ser Glu Arg Asp Leu Lys Lys Ser Val Leu Trp Leu Lys
225 230 235 240
Asp Ser Leu Gln Cys Thr Cys Glu Glu Met Asn Asp Ile Asn Ala Pro
245 250 255
Tyr Leu Val Met Gly Gln Lys Gln Gly Gly Glu Leu Val Ile Thr Ser
260 265 270
Val Lys Arg Trp Gln Lys Gly Gln Arg Glu Phe Lys Arg Ile Ser Arg
275 280 285
Ser Ile Arg Lys Leu Gln Cys
290 295
<210>3
<211>609
<212>PRT
<213>白蛋白
<400>3
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210>4
<211>1247
<212>PRT
<213>视黄醇结合蛋白3
<400>4
Met Met Arg Glu Trp Val Leu Leu Met Ser Val Leu Leu Cys Gly Leu
1 5 10 15
Ala Gly Pro Thr His Leu Phe Gln Pro Ser Leu Val Leu Asp Met Ala
20 25 30
Lys Val Leu Leu Asp Asn Tyr Cys Phe Pro Glu Asn Leu Leu Gly Met
35 40 45
Gln Glu Ala Ile Gln Gln Ala Ile Lys Ser His Glu Ile Leu Ser Ile
50 55 60
Ser Asp Pro Gln Thr Leu Ala Ser Val Leu Thr Ala Gly Val Gln Ser
65 70 75 80
Ser Leu Asn Asp Pro Arg Leu Val Ile Ser Tyr Glu Pro Ser Thr Pro
85 90 95
Glu Pro Pro Pro Gln Val Pro Ala Leu Thr Ser Leu Ser Glu Glu Glu
100 105 110
Leu Leu Ala Trp Leu Gln Arg Gly Leu Arg His Glu Val Leu Glu Gly
115 120 125
Asn Val Gly Tyr Leu Arg Val Asp Ser Val Pro Gly Gln Glu Val Leu
130 135 140
Ser Met Met Gly Glu Phe Leu Val Ala His Val Trp Gly Asn Leu Met
145 150 155 160
Gly Thr Ser Ala Leu Val Leu Asp Leu Arg His Cys Thr Gly Gly Gln
165 170 175
Val Ser Gly Ile Pro Tyr Ile Ile Ser Tyr Leu His Pro Gly Asn Thr
180 185 190
Ile Leu His Val Asp Thr Ile Tyr Asn Arg Pro Ser Asn Thr Thr Thr
195 200 205
Glu Ile Trp Thr Leu Pro Gln Val Leu Gly Glu Arg Tyr Gly Ala Asp
210 215 220
Lys Asp Val Val Val Leu Thr Ser Ser Gln Thr Arg Gly Val Ala Glu
225 230 235 240
Asp Ile Ala His Ile Leu Lys Gln Met Arg Arg Ala Ile Val Val Gly
245 250 255
Glu Arg Thr Gly Gly Gly Ala Leu Asp Leu Arg Lys Leu Arg Ile Gly
260 265 270
Glu Ser Asp Phe Phe Phe Thr Val Pro Val Ser Arg Ser Leu Gly Pro
275 280 285
Leu Gly Gly Gly Ser Gln Thr Trp Glu Gly Ser Gly Val Leu Pro Cys
290 295 300
Val Gly Thr Pro Ala Glu Gln Ala Leu Glu Lys Ala Leu Ala Ile Leu
305 310 315 320
Thr Leu Arg Ser Ala Leu Pro Gly Val Val His Cys Leu Gln Glu Val
325 330 335
Leu Lys Asp Tyr Tyr Thr Leu Val Asp Arg Val Pro Thr Leu Leu Gln
340 345 350
His Leu Ala Ser Met Asp Phe Ser Thr Val Val Ser Glu Glu Asp Leu
355 360 365
Val Thr Lys Leu Asn Ala Gly Leu Gln Ala Ala Ser Glu Asp Pro Arg
370 375 380
Leu Leu Val Arg Ala Ile Gly Pro Thr Glu Thr Pro Ser Trp Pro Ala
385 390 395 400
Pro Asp Ala Ala Ala Glu Asp Ser Pro Gly Val Ala Pro Glu Leu Pro
405 410 415
Glu Asp Glu Ala Ile Arg Gln Ala Leu Val Asp Ser Val Phe Gln Val
420 425 430
Ser Val Leu Pro Gly Asn Val Gly Tyr Leu Arg Phe Asp Ser Phe Ala
435 440 445
Asp Ala Ser Val Leu Gly Val Leu Ala Pro Tyr Val Leu Arg Gln Val
450 455 460
Trp Glu Pro Leu Gln Asp Thr Glu His Leu Ile Met Asp Leu Arg His
465 470 475 480
Asn Pro Gly Gly Pro Ser Ser Ala Val Pro Leu Leu Leu Ser Tyr Phe
485 490 495
Gln Gly Pro Glu Ala Gly Pro Val His Leu Phe Thr Thr Tyr Asp Arg
500 505 510
Arg Thr Asn Ile Thr Gln Glu His Phe Ser His Met Glu Leu Pro Gly
515 520 525
Pro Arg Tyr Ser Thr Gln Arg Gly Val Tyr Leu Leu Thr Ser His Arg
530 535 540
Thr Ala Thr Ala Ala Glu Glu Phe Ala Phe Leu Met Gln Ser Leu Gly
545 550 555 560
Trp Ala Thr Leu Val Gly Glu Ile Thr Ala Gly Asn Leu Leu His Thr
565 570 575
Arg Thr Val Pro Leu Leu Asp Thr Pro Glu Gly Ser Leu Ala Leu Thr
580 585 590
Val Pro Val Leu Thr Phe Ile Asp Asn His Gly Glu Ala Trp Leu Gly
595 600 605
Gly Gly Val Val Pro Asp Ala Ile Val Leu Ala Glu Glu Ala Leu Asp
610 615 620
Lys Ala Gln Glu Val Leu Glu Phe His Gln Ser Leu Gly Ala Leu Val
625 630 635 640
Glu Gly Thr Gly His Leu Leu Glu Ala His Tyr Ala Arg Pro Glu Val
645 650 655
Val Gly Gln Thr Ser Ala Leu Leu Arg Ala Lys Leu Ala Gln Gly Ala
660 665 670
Tyr Arg Thr Ala Val Asp Leu Glu Ser Leu Ala Ser Gln Leu Thr Ala
675 680 685
Asp Leu Gln Glu Val Ser Gly Asp His Arg Leu Leu Val Phe His Ser
690 695 700
Pro Gly Glu Leu Val Val Glu Glu Ala Pro Pro Pro Pro Pro Ala Val
705 710 715 720
Pro Ser Pro Glu Glu Leu Thr Tyr Leu Ile Glu Ala Leu Phe Lys Thr
725 730 735
Glu Val Leu Pro Gly Gln Leu Gly Tyr Leu Arg Phe Asp Ala Met Ala
740 745 750
Glu Leu Glu Thr Val Lys Ala Val Gly Pro Gln Leu Val Arg Leu Val
755 760 765
Trp Gln Gln Leu Val Asp Thr Ala Ala Leu Val Ile Asp Leu Arg Tyr
770 775 780
Asn Pro Gly Ser Tyr Ser Thr Ala Ile Pro Leu Leu Cys Ser Tyr Phe
785 790 795 800
Phe Glu Ala Glu Pro Arg Gln His Leu Tyr Ser Val Phe Asp Arg Ala
805 810 815
Thr Ser Lys Val Thr Glu Val Trp Thr Leu Pro Gln Val Ala Gly Gln
820 825 830
Arg Tyr Gly Ser His Lys Asp Leu Tyr Ile Leu Met Ser His Thr Ser
835 840 845
Gly Ser Ala Ala Glu Ala Phe Ala His Thr Met Gln Asp Leu Gln Arg
850 855 860
Ala Thr Val Ile Gly Glu Pro Thr Ala Gly Gly Ala Leu Ser Val Gly
865 870 875 880
Ile Tyr Gln Val Gly Ser Ser Pro Leu Tyr Ala Ser Met Pro Thr Gln
885 890 895
Met Ala Met Ser Ala Thr Thr Gly Lys Ala Trp Asp Leu Ala Gly Val
900 905 910
Glu Pro Asp Ile Thr Val Pro Met Ser Glu Ala Leu Ser Ile Ala Gln
915 920 925
Asp Ile Val Ala Leu Arg Ala Lys Val Pro Thr Val Leu Gln Thr Ala
930 935 940
Gly Lys Leu Val Ala Asp Asn Tyr Ala Ser Ala Glu Leu Gly Ala Lys
945 950 955 960
Met Ala Thr Lys Leu Ser Gly Leu Gln Ser Arg Tyr Ser Arg Val Thr
965 970 975
Ser Glu Val Ala Leu Ala Glu Ile Leu Gly Ala Asp Leu Gln Met Leu
980 985 990
Ser Gly Asp Pro His Leu Lys Ala Ala His Ile Pro Glu Asn Ala Lys
995 1000 1005
Asp Arg Ile Pro Gly Ile Val Pro Met Gln Ile Pro Ser Pro Glu Val
1010 1015 1020
Phe Glu Glu Leu Ile Lys Phe Ser Phe His Thr Asn Val Leu Glu Asp
1025 1030 1035 1040
Asn Ile Gly Tyr Leu Arg Phe Asp Met Phe Gly Asp Gly Glu Leu Leu
1045 1050 1055
Thr Gln Val Ser Arg Leu Leu Val Glu His Ile Trp Lys Lys Ile Met
1060 1065 1070
His Thr Asp Ala Met Ile Ile Asp Met Arg Phe Asn Ile Gly Gly Pro
1075 1080 1085
Thr Ser Ser Ile Pro Ile Leu Cys Ser Tyr Phe Phe Asp Glu Gly Pro
1090 1095 1100
Pro Val Leu Leu Asp Lys Ile Tyr Ser Arg Pro Asp Asp Ser Val Ser
1105 1110 1115 1120
Glu Leu Trp Thr His Ala Gln Val Val Gly Glu Arg Tyr Gly Ser Lys
1125 1130 1135
Lys Ser Met Val Ile Leu Thr Ser Ser Val Thr Ala Gly Thr Ala Glu
1140 1145 1150
Glu Phe Thr Tyr Ile Met Lys Arg Leu Gly Arg Ala Leu Val Ile Gly
1155 1160 1165
Glu Val Thr Ser Gly Gly Cys Gln Pro Pro Gln Thr Tyr His Val Asp
1170 1175 1180
Asp Thr Asn Leu Tyr Leu Thr Ile Pro Thr Ala Arg Ser Val Gly Ala
1185 1190 1195 1200
Ser Asp Gly Ser Ser Trp Glu Gly Val Gly Val Thr Pro His Val Val
1205 1210 1215
Val Pro Ala Glu Glu Ala Leu Ala Arg Ala Lys Glu Met Leu Gln His
1220 1225 1230
Asn Gln Leu Arg Val Lys Arg Ser Pro Gly Leu Gln Asp His Leu
1235 1240 1245
<210>5
<211>173
<212>PRT
<213>α-晶状体蛋白A链
<400>5
Met Asp Val Thr Ile Gln His Pro Trp Phe Lys Arg Thr Leu Gly Pro
1 5 10 15
Phe Tyr Pro Ser Arg Leu Phe Asp Gln Phe Phe Gly Glu Gly Leu Phe
20 25 30
Glu Tyr Asp Leu Leu Pro Phe Leu Ser Ser Thr Ile Ser Pro Tyr Tyr
35 40 45
Arg Gln Ser Leu Phe Arg Thr Val Leu Asp Ser Gly Ile Ser Glu Val
50 55 60
Arg Ser Asp Arg Asp Lys Phe Val Ile Phe Leu Asp Val Lys His Phe
65 70 75 80
Ser Pro Glu Asp Leu Thr Val Lys Val Gln Asp Asp Phe Val Glu Ile
85 90 95
His Gly Lys His Asn Glu Arg Gln Asp Asp His Gly Tyr Ile Ser Arg
100 105 110
Glu Phe His Arg Arg Tyr Arg Leu Pro Ser Asn Val Asp Gln Ser Ala
115 120 125
Leu Ser Cys Ser Leu Ser Ala Asp Gly Met Leu Thr Phe Cys Gly Pro
130 135 140
Lys Ile Gln Thr Gly Leu Asp Ala Thr His Ala Glu Arg Ala Ile Pro
145 150 155 160
Val Ser Arg Glu Glu Lys Pro Thr Ser Ala Pro Ser Ser
165 170
序列表
<110> 首尔大学校 产学协力团
韩国标准科学研究院
<120> 用于抑制血管生成的含有纳米颗粒-玻璃体基蛋白质复合物作为活性成分的组合物及其用途
<130> MPO17-089CN
<150> KR 10-2015-0099308
<151> 2015-07-13
<150> PCT/KR2016/007570
<151> 2016-07-12
<160> 5
<170> SIPOSequenceListing 1.0
<210> 1
<211> 678
<212> PRT
<213> Vitrin
<400> 1
Met Arg Thr Val Val Leu Thr Met Lys Ala Ser Val Ile Glu Met Phe
1 5 10 15
Leu Val Leu Leu Val Thr Gly Val His Ser Asn Lys Glu Thr Ala Lys
20 25 30
Lys Ile Lys Arg Pro Lys Phe Thr Val Pro Gln Ile Asn Cys Asp Val
35 40 45
Lys Ala Gly Lys Ile Ile Asp Pro Glu Phe Ile Val Lys Cys Pro Ala
50 55 60
Gly Cys Gln Asp Pro Lys Tyr His Val Tyr Gly Thr Asp Val Tyr Ala
65 70 75 80
Ser Tyr Ser Ser Val Cys Gly Ala Ala Val His Ser Gly Val Leu Asp
85 90 95
Asn Ser Gly Gly Lys Ile Leu Val Arg Lys Val Ala Gly Gln Ser Gly
100 105 110
Tyr Lys Gly Ser Tyr Ser Asn Gly Val Gln Ser Leu Ser Leu Pro Arg
115 120 125
Trp Arg Glu Ser Phe Ile Val Leu Glu Ser Lys Pro Lys Lys Gly Val
130 135 140
Thr Tyr Pro Ser Ala Leu Thr Tyr Ser Ser Ser Lys Ser Pro Ala Ala
145 150 155 160
Gln Ala Gly Glu Thr Thr Lys Ala Tyr Gln Arg Pro Pro Ile Pro Gly
165 170 175
Thr Thr Ala Gln Pro Val Thr Leu Met Gln Leu Leu Ala Val Thr Val
180 185 190
Ala Val Ala Thr Pro Thr Thr Leu Pro Arg Pro Ser Pro Ser Ala Ala
195 200 205
Ser Thr Thr Ser Ile Pro Arg Pro Gln Ser Val Gly His Arg Ser Gln
210 215 220
Glu Met Asp Leu Trp Ser Thr Ala Thr Tyr Thr Ser Ser Gln Asn Arg
225 230 235 240
Pro Arg Ala Asp Pro Gly Ile Gln Arg Gln Asp Pro Ser Gly Ala Ala
245 250 255
Phe Gln Lys Pro Val Gly Ala Asp Val Ser Leu Gly Leu Val Pro Lys
260 265 270
Glu Glu Leu Ser Thr Gln Ser Leu Glu Pro Val Ser Leu Gly Asp Pro
275 280 285
Asn Cys Lys Ile Asp Leu Ser Phe Leu Ile Asp Gly Ser Thr Ser Ile
290 295 300
Gly Lys Arg Arg Phe Arg Ile Gln Lys Gln Leu Leu Ala Asp Val Ala
305 310 315 320
Gln Ala Leu Asp Ile Gly Pro Ala Gly Pro Leu Met Gly Val Val Gln
325 330 335
Tyr Gly Asp Asn Pro Ala Thr His Phe Asn Leu Lys Thr His Thr Asn
340 345 350
Ser Arg Asp Leu Lys Thr Ala Ile Glu Lys Ile Thr Gln Arg Gly Gly
355 360 365
Leu Ser Asn Val Gly Arg Ala Ile Ser Phe Val Thr Lys Asn Phe Phe
370 375 380
Ser Lys Ala Asn Gly Asn Arg Ser Gly Ala Pro Asn Val Val Val Val
385 390 395 400
Met Val Asp Gly Trp Pro Thr Asp Lys Val Glu Glu Ala Ser Arg Leu
405 410 415
Ala Arg Glu Ser Gly Ile Asn Ile Phe Phe Ile Thr Ile Glu Gly Ala
420 425 430
Ala Glu Asn Glu Lys Gln Tyr Val Val Glu Pro Asn Phe Ala Asn Lys
435 440 445
Ala Val Cys Arg Thr Asn Gly Phe Tyr Ser Leu His Val Gln Ser Trp
450 455 460
Phe Gly Leu His Lys Thr Leu Gln Pro Leu Val Lys Arg Val Cys Asp
465 470 475 480
Thr Asp Arg Leu Ala Cys Ser Lys Thr Cys Leu Asn Ser Ala Asp Ile
485 490 495
Gly Phe Val Ile Asp Gly Ser Ser Ser Val Gly Thr Gly Asn Phe Arg
500 505 510
Thr Val Leu Gln Phe Val Thr Asn Leu Thr Lys Glu Phe Glu Ile Ser
515 520 525
Asp Thr Asp Thr Arg Ile Gly Ala Val Gln Tyr Thr Tyr Glu Gln Arg
530 535 540
Leu Glu Phe Gly Phe Asp Lys Tyr Ser Ser Lys Pro Asp Ile Leu Asn
545 550 555 560
Ala Ile Lys Arg Val Gly Tyr Trp Ser Gly Gly Thr Ser Thr Gly Ala
565 570 575
Ala Ile Asn Phe Ala Leu Glu Gln Leu Phe Lys Lys Ser Lys Pro Asn
580 585 590
Lys Arg Lys Leu Met Ile Leu Ile Thr Asp Gly Arg Ser Tyr Asp Asp
595 600 605
Val Arg Ile Pro Ala Met Ala Ala His Leu Lys Gly Val Ile Thr Tyr
610 615 620
Ala Ile Gly Val Ala Trp Ala Ala Gln Glu Glu Leu Glu Val Ile Ala
625 630 635 640
Thr His Pro Ala Arg Asp His Ser Phe Phe Val Asp Glu Phe Asp Asn
645 650 655
Leu His Gln Tyr Val Pro Arg Ile Ile Gln Asn Ile Cys Thr Glu Phe
660 665 670
Asn Ser Gln Pro Arg Asn
675
<210> 2
<211> 295
<212> PRT
<213> 分泌型卷曲相关蛋白2(Secreted frizzled-related protein 2)
<400> 2
Met Leu Gln Gly Pro Gly Ser Leu Leu Leu Leu Phe Leu Ala Ser His
1 5 10 15
Cys Cys Leu Gly Ser Ala Arg Gly Leu Phe Leu Phe Gly Gln Pro Asp
20 25 30
Phe Ser Tyr Lys Arg Ser Asn Cys Lys Pro Ile Pro Ala Asn Leu Gln
35 40 45
Leu Cys His Gly Ile Glu Tyr Gln Asn Met Arg Leu Pro Asn Leu Leu
50 55 60
Gly His Glu Thr Met Lys Glu Val Leu Glu Gln Ala Gly Ala Trp Ile
65 70 75 80
Pro Leu Val Met Lys Gln Cys His Pro Asp Thr Lys Lys Phe Leu Cys
85 90 95
Ser Leu Phe Ala Pro Val Cys Leu Asp Asp Leu Asp Glu Thr Ile Gln
100 105 110
Pro Cys His Ser Leu Cys Val Gln Val Lys Asp Arg Cys Ala Pro Val
115 120 125
Met Ser Ala Phe Gly Phe Pro Trp Pro Asp Met Leu Glu Cys Asp Arg
130 135 140
Phe Pro Gln Asp Asn Asp Leu Cys Ile Pro Leu Ala Ser Ser Asp His
145 150 155 160
Leu Leu Pro Ala Thr Glu Glu Ala Pro Lys Val Cys Glu Ala Cys Lys
165 170 175
Asn Lys Asn Asp Asp Asp Asn Asp Ile Met Glu Thr Leu Cys Lys Asn
180 185 190
Asp Phe Ala Leu Lys Ile Lys Val Lys Glu Ile Thr Tyr Ile Asn Arg
195 200 205
Asp Thr Lys Ile Ile Leu Glu Thr Lys Ser Lys Thr Ile Tyr Lys Leu
210 215 220
Asn Gly Val Ser Glu Arg Asp Leu Lys Lys Ser Val Leu Trp Leu Lys
225 230 235 240
Asp Ser Leu Gln Cys Thr Cys Glu Glu Met Asn Asp Ile Asn Ala Pro
245 250 255
Tyr Leu Val Met Gly Gln Lys Gln Gly Gly Glu Leu Val Ile Thr Ser
260 265 270
Val Lys Arg Trp Gln Lys Gly Gln Arg Glu Phe Lys Arg Ile Ser Arg
275 280 285
Ser Ile Arg Lys Leu Gln Cys
290 295
<210> 3
<211> 609
<212> PRT
<213> 白蛋白(Albumin)
<400> 3
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 4
<211> 1247
<212> PRT
<213> 视黄醇结合蛋白3(Retinol-binding protein 3)
<400> 4
Met Met Arg Glu Trp Val Leu Leu Met Ser Val Leu Leu Cys Gly Leu
1 5 10 15
Ala Gly Pro Thr His Leu Phe Gln Pro Ser Leu Val Leu Asp Met Ala
20 25 30
Lys Val Leu Leu Asp Asn Tyr Cys Phe Pro Glu Asn Leu Leu Gly Met
35 40 45
Gln Glu Ala Ile Gln Gln Ala Ile Lys Ser His Glu Ile Leu Ser Ile
50 55 60
Ser Asp Pro Gln Thr Leu Ala Ser Val Leu Thr Ala Gly Val Gln Ser
65 70 75 80
Ser Leu Asn Asp Pro Arg Leu Val Ile Ser Tyr Glu Pro Ser Thr Pro
85 90 95
Glu Pro Pro Pro Gln Val Pro Ala Leu Thr Ser Leu Ser Glu Glu Glu
100 105 110
Leu Leu Ala Trp Leu Gln Arg Gly Leu Arg His Glu Val Leu Glu Gly
115 120 125
Asn Val Gly Tyr Leu Arg Val Asp Ser Val Pro Gly Gln Glu Val Leu
130 135 140
Ser Met Met Gly Glu Phe Leu Val Ala His Val Trp Gly Asn Leu Met
145 150 155 160
Gly Thr Ser Ala Leu Val Leu Asp Leu Arg His Cys Thr Gly Gly Gln
165 170 175
Val Ser Gly Ile Pro Tyr Ile Ile Ser Tyr Leu His Pro Gly Asn Thr
180 185 190
Ile Leu His Val Asp Thr Ile Tyr Asn Arg Pro Ser Asn Thr Thr Thr
195 200 205
Glu Ile Trp Thr Leu Pro Gln Val Leu Gly Glu Arg Tyr Gly Ala Asp
210 215 220
Lys Asp Val Val Val Leu Thr Ser Ser Gln Thr Arg Gly Val Ala Glu
225 230 235 240
Asp Ile Ala His Ile Leu Lys Gln Met Arg Arg Ala Ile Val Val Gly
245 250 255
Glu Arg Thr Gly Gly Gly Ala Leu Asp Leu Arg Lys Leu Arg Ile Gly
260 265 270
Glu Ser Asp Phe Phe Phe Thr Val Pro Val Ser Arg Ser Leu Gly Pro
275 280 285
Leu Gly Gly Gly Ser Gln Thr Trp Glu Gly Ser Gly Val Leu Pro Cys
290 295 300
Val Gly Thr Pro Ala Glu Gln Ala Leu Glu Lys Ala Leu Ala Ile Leu
305 310 315 320
Thr Leu Arg Ser Ala Leu Pro Gly Val Val His Cys Leu Gln Glu Val
325 330 335
Leu Lys Asp Tyr Tyr Thr Leu Val Asp Arg Val Pro Thr Leu Leu Gln
340 345 350
His Leu Ala Ser Met Asp Phe Ser Thr Val Val Ser Glu Glu Asp Leu
355 360 365
Val Thr Lys Leu Asn Ala Gly Leu Gln Ala Ala Ser Glu Asp Pro Arg
370 375 380
Leu Leu Val Arg Ala Ile Gly Pro Thr Glu Thr Pro Ser Trp Pro Ala
385 390 395 400
Pro Asp Ala Ala Ala Glu Asp Ser Pro Gly Val Ala Pro Glu Leu Pro
405 410 415
Glu Asp Glu Ala Ile Arg Gln Ala Leu Val Asp Ser Val Phe Gln Val
420 425 430
Ser Val Leu Pro Gly Asn Val Gly Tyr Leu Arg Phe Asp Ser Phe Ala
435 440 445
Asp Ala Ser Val Leu Gly Val Leu Ala Pro Tyr Val Leu Arg Gln Val
450 455 460
Trp Glu Pro Leu Gln Asp Thr Glu His Leu Ile Met Asp Leu Arg His
465 470 475 480
Asn Pro Gly Gly Pro Ser Ser Ala Val Pro Leu Leu Leu Ser Tyr Phe
485 490 495
Gln Gly Pro Glu Ala Gly Pro Val His Leu Phe Thr Thr Tyr Asp Arg
500 505 510
Arg Thr Asn Ile Thr Gln Glu His Phe Ser His Met Glu Leu Pro Gly
515 520 525
Pro Arg Tyr Ser Thr Gln Arg Gly Val Tyr Leu Leu Thr Ser His Arg
530 535 540
Thr Ala Thr Ala Ala Glu Glu Phe Ala Phe Leu Met Gln Ser Leu Gly
545 550 555 560
Trp Ala Thr Leu Val Gly Glu Ile Thr Ala Gly Asn Leu Leu His Thr
565 570 575
Arg Thr Val Pro Leu Leu Asp Thr Pro Glu Gly Ser Leu Ala Leu Thr
580 585 590
Val Pro Val Leu Thr Phe Ile Asp Asn His Gly Glu Ala Trp Leu Gly
595 600 605
Gly Gly Val Val Pro Asp Ala Ile Val Leu Ala Glu Glu Ala Leu Asp
610 615 620
Lys Ala Gln Glu Val Leu Glu Phe His Gln Ser Leu Gly Ala Leu Val
625 630 635 640
Glu Gly Thr Gly His Leu Leu Glu Ala His Tyr Ala Arg Pro Glu Val
645 650 655
Val Gly Gln Thr Ser Ala Leu Leu Arg Ala Lys Leu Ala Gln Gly Ala
660 665 670
Tyr Arg Thr Ala Val Asp Leu Glu Ser Leu Ala Ser Gln Leu Thr Ala
675 680 685
Asp Leu Gln Glu Val Ser Gly Asp His Arg Leu Leu Val Phe His Ser
690 695 700
Pro Gly Glu Leu Val Val Glu Glu Ala Pro Pro Pro Pro Pro Ala Val
705 710 715 720
Pro Ser Pro Glu Glu Leu Thr Tyr Leu Ile Glu Ala Leu Phe Lys Thr
725 730 735
Glu Val Leu Pro Gly Gln Leu Gly Tyr Leu Arg Phe Asp Ala Met Ala
740 745 750
Glu Leu Glu Thr Val Lys Ala Val Gly Pro Gln Leu Val Arg Leu Val
755 760 765
Trp Gln Gln Leu Val Asp Thr Ala Ala Leu Val Ile Asp Leu Arg Tyr
770 775 780
Asn Pro Gly Ser Tyr Ser Thr Ala Ile Pro Leu Leu Cys Ser Tyr Phe
785 790 795 800
Phe Glu Ala Glu Pro Arg Gln His Leu Tyr Ser Val Phe Asp Arg Ala
805 810 815
Thr Ser Lys Val Thr Glu Val Trp Thr Leu Pro Gln Val Ala Gly Gln
820 825 830
Arg Tyr Gly Ser His Lys Asp Leu Tyr Ile Leu Met Ser His Thr Ser
835 840 845
Gly Ser Ala Ala Glu Ala Phe Ala His Thr Met Gln Asp Leu Gln Arg
850 855 860
Ala Thr Val Ile Gly Glu Pro Thr Ala Gly Gly Ala Leu Ser Val Gly
865 870 875 880
Ile Tyr Gln Val Gly Ser Ser Pro Leu Tyr Ala Ser Met Pro Thr Gln
885 890 895
Met Ala Met Ser Ala Thr Thr Gly Lys Ala Trp Asp Leu Ala Gly Val
900 905 910
Glu Pro Asp Ile Thr Val Pro Met Ser Glu Ala Leu Ser Ile Ala Gln
915 920 925
Asp Ile Val Ala Leu Arg Ala Lys Val Pro Thr Val Leu Gln Thr Ala
930 935 940
Gly Lys Leu Val Ala Asp Asn Tyr Ala Ser Ala Glu Leu Gly Ala Lys
945 950 955 960
Met Ala Thr Lys Leu Ser Gly Leu Gln Ser Arg Tyr Ser Arg Val Thr
965 970 975
Ser Glu Val Ala Leu Ala Glu Ile Leu Gly Ala Asp Leu Gln Met Leu
980 985 990
Ser Gly Asp Pro His Leu Lys Ala Ala His Ile Pro Glu Asn Ala Lys
995 1000 1005
Asp Arg Ile Pro Gly Ile Val Pro Met Gln Ile Pro Ser Pro Glu Val
1010 1015 1020
Phe Glu Glu Leu Ile Lys Phe Ser Phe His Thr Asn Val Leu Glu Asp
1025 1030 1035 1040
Asn Ile Gly Tyr Leu Arg Phe Asp Met Phe Gly Asp Gly Glu Leu Leu
1045 1050 1055
Thr Gln Val Ser Arg Leu Leu Val Glu His Ile Trp Lys Lys Ile Met
1060 1065 1070
His Thr Asp Ala Met Ile Ile Asp Met Arg Phe Asn Ile Gly Gly Pro
1075 1080 1085
Thr Ser Ser Ile Pro Ile Leu Cys Ser Tyr Phe Phe Asp Glu Gly Pro
1090 1095 1100
Pro Val Leu Leu Asp Lys Ile Tyr Ser Arg Pro Asp Asp Ser Val Ser
1105 1110 1115 1120
Glu Leu Trp Thr His Ala Gln Val Val Gly Glu Arg Tyr Gly Ser Lys
1125 1130 1135
Lys Ser Met Val Ile Leu Thr Ser Ser Val Thr Ala Gly Thr Ala Glu
1140 1145 1150
Glu Phe Thr Tyr Ile Met Lys Arg Leu Gly Arg Ala Leu Val Ile Gly
1155 1160 1165
Glu Val Thr Ser Gly Gly Cys Gln Pro Pro Gln Thr Tyr His Val Asp
1170 1175 1180
Asp Thr Asn Leu Tyr Leu Thr Ile Pro Thr Ala Arg Ser Val Gly Ala
1185 1190 1195 1200
Ser Asp Gly Ser Ser Trp Glu Gly Val Gly Val Thr Pro His Val Val
1205 1210 1215
Val Pro Ala Glu Glu Ala Leu Ala Arg Ala Lys Glu Met Leu Gln His
1220 1225 1230
Asn Gln Leu Arg Val Lys Arg Ser Pro Gly Leu Gln Asp His Leu
1235 1240 1245
<210> 5
<211> 173
<212> PRT
<213> α-晶状体蛋白A链(Alpha-crystallin A chain)
<400> 5
Met Asp Val Thr Ile Gln His Pro Trp Phe Lys Arg Thr Leu Gly Pro
1 5 10 15
Phe Tyr Pro Ser Arg Leu Phe Asp Gln Phe Phe Gly Glu Gly Leu Phe
20 25 30
Glu Tyr Asp Leu Leu Pro Phe Leu Ser Ser Thr Ile Ser Pro Tyr Tyr
35 40 45
Arg Gln Ser Leu Phe Arg Thr Val Leu Asp Ser Gly Ile Ser Glu Val
50 55 60
Arg Ser Asp Arg Asp Lys Phe Val Ile Phe Leu Asp Val Lys His Phe
65 70 75 80
Ser Pro Glu Asp Leu Thr Val Lys Val Gln Asp Asp Phe Val Glu Ile
85 90 95
His Gly Lys His Asn Glu Arg Gln Asp Asp His Gly Tyr Ile Ser Arg
100 105 110
Glu Phe His Arg Arg Tyr Arg Leu Pro Ser Asn Val Asp Gln Ser Ala
115 120 125
Leu Ser Cys Ser Leu Ser Ala Asp Gly Met Leu Thr Phe Cys Gly Pro
130 135 140
Lys Ile Gln Thr Gly Leu Asp Ala Thr His Ala Glu Arg Ala Ile Pro
145 150 155 160
Val Ser Arg Glu Glu Lys Pro Thr Ser Ala Pro Ser Ser
165 170

Claims (8)

1.用于抑制血管生成的药物组合物，所述药物组合物包含作为活性成分的由纳米颗粒和围绕所述纳米颗粒表面的玻璃体基蛋白质组成的复合物。
2.根据权利要求1所述的药物组合物，其中所述纳米颗粒是金或二氧化硅。
3.根据权利要求1所述的药物组合物，其中所述纳米颗粒具有20nm至100nm的直径。
4.根据权利要求1所述的药物组合物，其中所述血管生成参与早产儿视网膜病变、糖尿病性黄斑水肿(DME)、糖尿病视网膜病变、中心性浆液性(脉络膜)视网膜病、年龄相关性黄斑变性或增殖性视网膜病变。
5.根据权利要求1所述的药物组合物，其中所述玻璃体基蛋白质包含选自由vitrin、分泌型卷曲相关蛋白2、血清白蛋白、视黄醇结合蛋白3和α-晶状体蛋白A链组成的组中的一种或多种。
6.用于预防或治疗视网膜疾病的药物组合物，所述药物组合物包含根据权利要求1至5中任一项所述的组合物作为活性成分。
7.根据权利要求6所述的药物组合物，其中所述视网膜疾病选自：早产儿视网膜病变、糖尿病性黄斑水肿(DME)、糖尿病视网膜病变、中心性浆液性(脉络膜)视网膜病、年龄相关性黄斑变性和增殖性视网膜病变。
8.筛选适用于治疗视网膜疾病的蛋白质的方法，所述方法包括以下过程：
(1)将纳米颗粒体外注入玻璃体中；
(2)分离玻璃体中的所述纳米颗粒和蛋白质的复合物；
(3)将所述复合物与血管内皮生长因子(VEGF)结合；和
(4)选择与所述VEGF结合的复合物。
CN201680052488.XA 2015-07-13 2016-07-12 用于抑制血管生成的含有纳米颗粒-玻璃体基蛋白质复合物作为活性成分的组合物及其用途 Active CN108348544B (zh)

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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180140626A1 (en) * 2015-05-14 2018-05-24 Joslin Diabetes Center, Inc. Retinol-binding protein 3 (rbp3) as a protective factor in non-diabetic retinal degeneration
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060222595A1 (en) * 2005-03-31 2006-10-05 Priyabrata Mukherjee Nanoparticles for therapeutic and diagnostic applications
WO2009040811A3 (en) * 2007-09-24 2010-03-04 Bar-Ilan University Polymer nanoparticles coated by magnetic metal oxide and uses thereof
US20110104069A1 (en) * 2009-10-30 2011-05-05 The Ohio State University Multi-functional biodegradable particles for selectable targeting, imaging, and therapeutic delivery and use thereof for treating ocular disorders
CN102427728A (zh) * 2009-03-13 2012-04-25 阿布拉科斯生物科学有限公司 用硫代秋水仙碱衍生物进行联合治疗
WO2012054564A2 (en) * 2010-10-19 2012-04-26 The Curators Of The University Of Missouri Anti-vegf antibody/fragment conjugated gold nanoparticles, and fabrication and therapeutic methods
AU2013204188A1 (en) * 2005-02-18 2013-05-16 Abraxis Bioscience, Llc Combinations and modes of administration of therapeutic agents and combination therapy
WO2014107596A1 (en) * 2013-01-03 2014-07-10 Washington University Compositions and methods for polynucleotide transfection
CN104470534A (zh) * 2012-05-21 2015-03-25 科罗拉多大学董事会 用于治疗退变性病症的ledgf肽及其制剂

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ511762A (en) * 1993-07-19 2003-09-26 Univ British Columbia Anti-angiogenic compositions and methods of use
PL207175B1 (pl) * 2001-08-01 2010-11-30 Merck Patent Gmbh Zastosowanie inhibitorów integryny do wytwarzania kompozycji farmaceutycznych do zapobiegania i/lub terapii chorób oczu
EP1453546A2 (en) * 2001-12-04 2004-09-08 Nanospectra Biosciences, Inc. Treatment of angiogenesis disorders using targeted nanoparticles
KR100990810B1 (ko) * 2001-12-21 2010-10-29 알콘, 인코퍼레이티드 안과용 약물 및 이과용 약물을 위한 담체로서 합성 무기 나노입자의 용도
JP4842514B2 (ja) * 2002-03-20 2011-12-21 エラン ファーマ インターナショナル，リミティド 血管新生抑制剤のナノ粒子組成物
ES2389828T3 (es) * 2007-04-13 2012-11-02 Abraxis Bioscience, Inc. Composiciones que comprenden polipéptidos SPARC
KR101415221B1 (ko) * 2012-08-07 2014-07-09 한국표준과학연구원 무기 나노입자를 유효성분으로 함유하는 혈관 신생 관련 질환의 예방 및 치료용 조성물
WO2014197892A1 (en) * 2013-06-07 2014-12-11 The Johns Hopkins University A biomimetic peptide and biodegradable delivery platform for the treatment of angiogenesis- and lymphangiogenesis-dependent diseases
US10183079B2 (en) * 2016-03-18 2019-01-22 Wisconsin Alumni Research Foundation Hydrogel microspheres containing peptide ligands for growth factor regulation in blood products

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2013204188A1 (en) * 2005-02-18 2013-05-16 Abraxis Bioscience, Llc Combinations and modes of administration of therapeutic agents and combination therapy
US20060222595A1 (en) * 2005-03-31 2006-10-05 Priyabrata Mukherjee Nanoparticles for therapeutic and diagnostic applications
WO2009040811A3 (en) * 2007-09-24 2010-03-04 Bar-Ilan University Polymer nanoparticles coated by magnetic metal oxide and uses thereof
CN102427728A (zh) * 2009-03-13 2012-04-25 阿布拉科斯生物科学有限公司 用硫代秋水仙碱衍生物进行联合治疗
US20110104069A1 (en) * 2009-10-30 2011-05-05 The Ohio State University Multi-functional biodegradable particles for selectable targeting, imaging, and therapeutic delivery and use thereof for treating ocular disorders
WO2012054564A2 (en) * 2010-10-19 2012-04-26 The Curators Of The University Of Missouri Anti-vegf antibody/fragment conjugated gold nanoparticles, and fabrication and therapeutic methods
CN104470534A (zh) * 2012-05-21 2015-03-25 科罗拉多大学董事会 用于治疗退变性病症的ledgf肽及其制剂
WO2014107596A1 (en) * 2013-01-03 2014-07-10 Washington University Compositions and methods for polynucleotide transfection

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
MARINA A.DOBROVOLSKAIA ET AL.: "Interaction of colloidal gold nanoparticles with human blood: effects on particle size and analysis of plasma protein binding profiles", 《NANOMEDICINE: NANOTECHNOLOGY, BIOLOGY AND MEDICINE》 *
REYHANEH VARSHOCHIAN ET AL.: "Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment", 《JOURNAL OF BIOMEDICAL MATERIALS RESEARCH》 *
S. RAGHAVA ET AL.: "Intravenous Transferrin, RGD Peptide, and Dual Targeted Nanoparticles Enhance VEGF Intraceptor Gene Delivery to Laser Induced CNV", 《GENE THERAPY》 *
SHREYA GOEL ET AL.: "VEGF121-Conjugated Mesoporous Silica Nanoparticle: A Tumor Targeted Drug Delivery System", 《ACS APPL. MATER. INTERFACES》 *
TENZER S ET AL.: "Nanoparticle size is a critical physicochemical determinant of the human blood plasma corona: a comprehensive quantitative proteomic analysis", 《ACS NANO.》 *

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