CN111132991A - 用于抑制血管生成的肽及其用途 - Google Patents
用于抑制血管生成的肽及其用途 Download PDFInfo
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- CN111132991A CN111132991A CN201880061301.1A CN201880061301A CN111132991A CN 111132991 A CN111132991 A CN 111132991A CN 201880061301 A CN201880061301 A CN 201880061301A CN 111132991 A CN111132991 A CN 111132991A
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Abstract
本发明涉及一种具有血管生成抑制活性的新的肽，并且涉及所述肽在治疗或预防过度血管生成相关疾病中的用途。特别地，根据本发明的新的肽与血管内皮生长因子(VEGF)竞争结合VEGF受体，并且可以显著抑制血管内皮细胞的增殖、迁移和分化，从而可有效地用作用于预防或治疗由过度血管生成引起的疾病的组合物或功能性保健食品中的活性成分，所述疾病例如为黄斑变性、肿瘤、关节炎或银屑病。
Description
技术领域
本发明涉及具有血管生成抑制活性的新的肽，以及肽在涉及治疗或预防与过度血管生成相关的疾病中的用途。
背景技术
血管生成为向组织或器官提供新生血管的生物学过程，并且具体而言，血管生成是指由现有的微血管产生新生的毛细血管，并且血管生成是生长之后在体内产生血管的基本过程。人体中通常观察到的生理性血管生成仅在非常有限的情况下发生，例如胚胎和胎儿的发育、子宫的成熟、胎盘的增殖、黄体的形成和伤口愈合，并且即使在此时，如果也非常严格地调节生理性血管生成从而实现了所需功能，那么血管生成停止。新生血管的产生受血管生成调节因子的密切调节，并且已报道由于血管生成刺激因子的上调与血管生成抑制因子的下调之间的总体平衡，血管生成的表型发生了改变(Folkman J.,Nat.Med.,1(1):27-31(1995))。
产生新生血管的过程非常复杂和精细，但总体而言，该过程如下。首先，当血管生成激动剂传递到现有血管时，血管扩张并且膜渗透性增加。第二，纤维蛋白通过扩张的血管从血管中释放出来，然后沉积在血管周围的细胞质基质上。第三，激活分解现有血管的基底膜的酶，并且破坏基底膜，并且从其间的血管中释放内皮细胞，然后内皮细胞由周围细胞的基质增殖并迁移。最后，排列成行的内皮细胞形成管以产生新生血管(Risau W.,Nature,386(6626):671-674(1997))。
在很大程度上，作为最具代表性的疾病，可以将与以病理状态出现的血管生成相关的疾病分为诸如关节炎之类的炎症性疾病、诸如糖尿病性视网膜病变之类的眼科疾病、诸如银屑病之类的皮肤病和癌症(Folkman J.,Nat.Med.,1(1):27-31(1995))。由血管生成引起的眼科疾病包括以下疾病，例如黄斑变性，糖尿病性视网膜病变(其中视网膜中的毛细血管侵入玻璃体并且最终患者由于糖尿病的并发症而失明)，早产儿的视网膜病变和新生血管性青光眼等，并且全世界每年有数百万人由于这些疾病而失明。此外，关节炎由自身免疫异常引起，但已知在疾病发展的过程中，在滑膜腔中引起的慢性炎症会诱导血管生成，并且关节炎是当新生毛细血管侵入关节并破坏软骨时引起的疾病。此外，银屑病是一种发生在皮肤中的慢性增殖性疾病，并且对于快速增殖，因为需要供应大量血液，所以必须活跃地发生血管生成。
同时，促血管生成因子中的血管内皮生长因子(VEGF)激活了各种信号传导链反应，并且在诱导内皮细胞的增殖、迁移和分化中发挥作用。因此，可通过使用VEGF的中和抗体和信号抑制剂来抑制VEGF的生物活性和信号传导链反应，从而成为能够治疗与血管生成相关的各种疾病的治疗策略。
然而，尽管靶向VEGF或VEGF受体的血管生成抑制药物可以治疗多种与异常血管生成相关的疾病，但是仍然没有已知的与VEGF竞争结合VEGF受体并显著抑制血管内皮细胞的增殖、迁移和分化的肽。
发明内容
[技术问题]
本发明的目的是提供一种用于抑制血管生成的新的肽。
本发明的另一个目的是提供该新的肽在预防或治疗血管生成相关疾病中的用途。
[技术方案]
为了实现上述目的，本发明的一个方面提供了一种用于抑制血管生成的肽，该肽包含由SEQ ID NO:1或2表示的氨基酸序列。
本发明的另一方面提供了一种用于预防或治疗血管生成相关疾病的药物组合物，该药物组合物包含所述肽作为活性成分。
本发明的又一方面提供了一种用于预防或改善血管生成相关疾病的功能性保健食品，该功能性保健食品包含所述肽作为活性成分。
[有利效果]
根据本发明，所述新的肽与血管内皮生长因子(VEGF)竞争结合VEGF受体，并且显著抑制血管内皮细胞的增殖、迁移和分化，从而可有效地用作用于预防或治疗由过度血管生成引起的疾病的组合物中的活性成分。
然而，本发明的效果不限于上述效果，并且本领域技术人员从以下描述中将清楚地理解未提及的其他效果。
附图说明
图1和2分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ ID NO:2的氨基酸序列的肽抑制血管内皮细胞的增殖的效果的结果的图。
图3(a)、3(b)、4(a)和4(b)分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ ID NO:2的氨基酸序列的肽抑制血管内皮细胞的分化的效果的结果的图示和图。
图5和6分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ ID NO:2的氨基酸序列的肽抑制由VEGF诱导的细胞信号传导途径的效果的结果的图示。
图7和8分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ ID NO:2的氨基酸序列的肽改变eNOS蛋白的表达水平的效果的结果的图示。
图9和10分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ IDNO:2的氨基酸序列的肽改变BAX蛋白的表达水平的变化的效果的结果的图示。
图11和12分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ IDNO:2的氨基酸序列的肽是否与VEGF受体结合的结果的图。
图13和14分别为示出了证实具有SEQ ID NO:1的氨基酸序列的肽和具有SEQ IDNO:2的氨基酸序列的肽是否与VEGF竞争结合VEGF受体的结果的图。
在图1至14中，“VEGF+SEQ ID NO:1”表示用VEGF和具有SEQ ID NO:1的氨基酸序列的肽这两者处理的组，“VEGF+SEQ ID NO:2”表示用VEGF和具有SEQ ID NO:2的氨基酸序列的肽这两者处理的组，并且“VEGF+舒尼替尼”或“VEGF+Suni”表示用VEGF和舒尼替尼这两者处理的组。
具体实施方式
在下文中，将详细描述本发明。
1.用于抑制血管生成的肽
本发明的一个方面提供了一种具有血管生成抑制活性的新的肽。
肽是指由通过肽键连接的两个或更多个氨基酸组成的聚合物，并且肽的缺点在于，由于肽本身的尺寸太大，因此不能将肽有效地引入到靶组织或靶细胞中，并且由于半衰期短，因此肽在短时间内会在体内消失。本发明的肽由20个以下、优选15个以下、更优选10个以下的具有血管生成抑制活性的氨基酸组成。
本发明的新的肽可以包含SEQ ID NO:1或SEQ ID NO:2的氨基酸序列，并且可以是在不影响肽的血管生成抑制活性的范围内，通过氨基酸残基的缺失、插入、置换或组合而得到的具有不同序列的氨基酸的变体或片段。不改变肽整体的血管生成抑制活性的在肽水平上的氨基酸交换在本领域中是已知的。在一些情况下，可以通过磷酸化、硫酸化、丙烯酸酯化、糖基化、甲基化、法尼基化等修饰氨基酸交换。因此，本发明包括所具有的氨基酸序列与具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽基本上相同的肽，以及该肽的变体或活性片段。基本上相同的蛋白是指与SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的序列同源性为75％或以上，优选为80％或以上，更优选为90％或以上，最优选为95％或以上的氨基酸序列。此外，肽还可包括为了特定目的制备的氨基酸序列，从而增加靶向序列、标签、标记的残基、半衰期或肽稳定性。
可以通过本领域公知的各种方法获得本发明的肽。例如，可以通过使用多核苷酸重组和蛋白表达系统制备肽，或者由通过诸如肽合成、无细胞蛋白合成等的化学合成在体外合成制备肽。
此外，为了获得更好的化学稳定性、增强的药理学性质(半衰期、吸收性、效价、功效等)、修饰的特异性(例如，宽的生物活性谱)和降低的抗原性，保护基团可以结合至肽的N端或C端。优选地，保护基可为乙酰基、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)，但可以包括任何可以增强肽的修饰、特别是肽的稳定性的成分，对保护基团没有限制。
“肽的稳定性”不仅是指保护本发明的肽在体内免受蛋白裂解酶的攻击的体内稳定性，而且还指储存稳定性(例如，室温储存稳定性)。
为了证实本发明的肽抑制血管内皮细胞的增殖和分化的效果，在本发明的一个具体的示例实施方案中，用具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽处理血管内皮细胞，然后证实血管内皮细胞的增殖和分化的程度。结果证实，由VEGF诱导的血管内皮细胞的增殖和分化减少取决于是否经过本发明的肽的处理(参见图1至4)。
此外，为了证实本发明的肽抑制由VEGF诱导的细胞信号传导途径的效果，在本发明的一个具体的示例性实施方案中，用具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽对血管内皮细胞进行处理，然后证实由VEGF诱导的VEGF受体(VEGFR2)、ERK、AKT和p38的磷酸化的变化。结果证实，本发明的肽显著抑制了由VEGF诱导的VEGFR2、ERK、AKT和p38的磷酸化(参见图5和6)。
此外，为了证实本发明的肽抑制血管内皮细胞的迁移的效果，在本发明的一个具体的示例性实施方案中，取决于具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽对血管内皮细胞的处理，证实了血管内皮细胞迁移标记物“eNOS”的表达水平的变化。结果证实，本发明的肽浓度依赖性地降低了因VEGF处理而增加的eNOS表达(参见图7和8)。
此外，为了证实本发明的肽对因VEGF而表达降低的促细胞凋亡蛋白的效果，在本发明的具体的示例性实施方案中，通过证实根据具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽对血管内皮细胞的处理而引起的BAX蛋白的表达水平的变化，结果证实了VEGF降低了BAX蛋白(其为诱导细胞凋亡的蛋白)的表达，而在用本发明的肽处理的组中，BAX蛋白的表达浓度依赖性地增加(参见图9和10)。
此外，为了证实本发明的肽竞争性结合VEGF受体，在本发明的具体的示例性实施方案中，通过证实具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽是否与VEGF受体结合，以及所述肽是否与VEGF竞争结合VEGF受体，结果证实了本发明的肽与VEGF竞争结合VEGFR2(参见图13和14)。
因此，因为本发明的肽与VEGF竞争结合VEGF受体，并且显著抑制血管内皮细胞的增殖、迁移和分化，所以显而易见的是，肽具有有效抑制血管生成的活性，因此，本发明的肽可有效地用作抑制过度血管生成的组合物的活性成分。
2.用于治疗或预防血管生成相关疾病的药物组合物
本发明的另一方面提供了一种用于预防或治疗血管生成相关疾病的药物组合物，该药物组合物包含具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽作为活性成分。
包含SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽与“1.用于抑制血管生成的肽”的部分中描述的肽相同，并且详细的描述引用了“1.用于抑制血管生成的肽”的部分。在下文中，将仅描述用于治疗血管生成相关疾病的药物组合物的独特构成。
血管生成相关疾病是指由异常发展的血管生成引起的疾病，并且包括癌症、糖尿病性视网膜病变、早产儿视网膜病变、新生血管性青光眼、黑素瘤、增殖性视网膜病变、湿性黄斑变性、银屑病、血友病性关节炎、动脉粥样硬化斑块的毛细血管增生、瘢痕瘤、伤口肉芽、血管粘连、类风湿性关节炎、骨关节炎、自身免疫性疾病、克罗恩病、再狭窄症、动脉粥样硬化、猫抓病、溃疡、肾小球肾炎、糖尿病性肾病、恶性神经症、血栓性微血管病和肾小球病。
因此，因为通过抑制血管生成可以预防或治疗由血管生成引起的疾病，所以包含本发明的肽作为活性成分的组合物可以有效地用于治疗血管生成相关疾病，其中本发明的肽与VEGF竞争结合VEGF受体并且显著抑制血管内皮细胞的增殖、迁移和分化。
另一方面，可以在药学可接受的载体中携带本发明的肽，例如胶体悬浮液、粉末、生理盐水、脂质、脂质体、微球或球形纳米颗粒。这些肽可以与载体形成复合物或与复合物相关，并且可以通过使用本领域已知的携带体系在体内携带，所述本领域已知的携带体系例如为脂质、脂质体、微粒、金、纳米颗粒、聚合物、缩合试剂、多糖、聚氨基酸、树状聚合物、皂苷、吸附增强物质或脂肪酸。
此外，药学可接受的载体可以包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、金合欢胶、磷酸钙、海藻酸盐、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，以上通常用于制备，但不限于此。此外，除上述成分以外，药物组合物还可以包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。
本发明的药物组合物可以根据所需方法口服施用或肠胃外施用(例如，肌内给药、静脉内给药、腹腔内给药、皮下给药、皮内给药或局部给药)，并且剂量根据患者的状况和体重、疾病的程度、药物形式以及施用的途径和时间而变化，但是可以由本领域技术人员适当地选择。
以药学有效量施用本发明的药物组合物。在本发明中，“药学有效量”是指以适用于医学治疗的合理的效益/风险比治疗疾病的足够的量，并且可以根据包括患者的疾病的类型和严重程度、药品的活性、对药品的敏感性、施用的时间、施用的途径、排放速率、治疗的持续时间和同时使用的药物在内的因素以及医学领域中公知的其他因素确定有效量水平。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血管生成抑制剂联合施用，并且可以与常规治疗剂同时施用、单独施用或依次施用，并且可以单次或多次施用。重要的是通过考虑所有因素，从而施用能够获得最大效果而没有副作用的最小量，并且这可以由本领域技术人员容易地确定。
具体而言，本发明的药物组合物的有效剂量可以根据患者的年龄、性别、状况和体重，活性成分在体内的吸收，失活速率，排泄速率，疾病类型和组合使用的药品而变化，并且可以根据施用的途径、肥胖症的严重程度、性别、体重、年龄等而增加或减少。例如，可以以每天每kg患者体重约0.0001μg至500mg，优选0.01μg至100mg施用本发明的肽。
3.改善血管生成相关疾病的功能性保健食品
本发明的又一方面提供了一种用于预防或改善血管生成相关疾病的功能性保健食品，该功能性保健食品包含具有SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽作为活性成分。
包含SEQ ID NO:1或SEQ ID NO:2的氨基酸序列的肽与“1.用于抑制血管生成的肽”的部分中描述的肽相同，并且详细的描述引用了“1.用于抑制血管生成的肽”的部分。在下文中，将仅描述功能性保健食品的独特构成。
与药物组合物一样，因为可以通过抑制血管生成来预防或治疗由血管生成引起的疾病，所以包含本发明的肽作为活性成分的功能性保健食品可以有效地用于预防或改善血管生成相关疾病，其中本发明的肽与VEGF竞争结合VEGF受体并且显著抑制血管内皮细胞的增殖、迁移和分化。
功能性保健食品可在相应疾病发作之前或之后与治疗药品同时使用或分别使用，以便预防或改善疾病。
在本发明的功能性保健食品中，活性成分可以直接添加到食品中，或者将活性成分与其他食品或食品成分一起使用，并且可以根据一般方法适当地使用。活性成分的混合量可以根据其使用目的(用于预防或改善)适当地确定。通常，在制备食品或饮品时，本发明的组合物的添加量优选为原料的15重量％以下，更优选为10重量％以下。然而，在为了健康和卫生或健康调节的目的而长期摄取的情况下，该添加量可以等于或低于上述范围。
除活性成分以外，本发明的保健功能性食品还可以包含其他成分作为所需成分，没有特别地限制。例如，与一般饮品一样，可以包含各种调味剂或天然碳水化合物作为附加成分。上述天然碳水化合物的实例可以包括常规的糖，例如：单糖，如葡萄糖、果糖等；二糖，如麦芽糖、蔗糖等；以及多糖，如糊精、环糊精等；和糖醇，如木糖醇、山梨糖醇、赤藓糖醇等。作为上述以外的调味剂，可以优选使用天然调味剂(索马甜、甜叶菊提取物(例如，甜叶菊甙A、甘草甜素等))和合成调味剂(糖精、天冬甜素等)。天然碳水化合物的比例可以通过本领域技术人员的选择适当地确定。
此外，本发明的功能性保健食品可以包含各种营养素、维生素、矿物质(电解质)、诸如合成调味剂和天然调味剂之类的调味剂、着色剂和增味剂(奶酪、巧克力等)、果胶酸及其盐、藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、用于碳酸饮料的碳酸化剂等。这些成分可以单独使用或组合使用，并且这些添加剂的比例也可以由本领域技术人员适当地选择。
在下文中，通过实施例和实验例对本发明进行详细说明。
然而，以下实施例和实验例仅是对本发明的说明，并且本发明的内容不限于以下实施例和实验例。
[制备例1]肽的制备
使用自动肽合成仪(Milligen 9050，Millipore，美国)分别合成具有下表1所示的SEQ ID NO:1的氨基酸序列的肽和具有下表1所示的SEQ ID NO:2的氨基酸序列的肽，并且分别使用C18反相高效液相色谱(HPLC)(Waters Associates，美国)纯化这些合成的肽。柱使用ACQUITY UPLC BEH300 C18(2.1mm×100mm，1.7μm，Waters Co，美国)。
[表1]
| SEQ ID NO. | 肽序列 |
| 1 | NKNFGYDLYR |
| 2 | IHGTYKELL |
[实验例1]抑制血管内皮细胞的增殖的效果的证实
为了证实抑制血管内皮细胞的增殖的效果，分别用制备例1中制备的肽对血管内皮细胞进行处理，然后进行MTT分析。
具体而言，将人脐静脉内皮细胞(HUVEC)以4×103个细胞/孔的密度接种在96孔板中，然后孵育过夜。此后，在将培养基更换为添加了1％血清的培养基后，分别用VEGF(20ng/ml)和各浓度的本发明的肽进行处理，并且孵育3天。但是，将2μm的舒尼替尼用作阳性对照组。
此外，为了证实抑制增殖的效果，在各孔中添加4mg/ml的噻唑蓝溴化四唑(MTT)溶液，通过DMSO处理溶解反应4小时后产生的甲
然后使用酶标仪测定560nm的波长处的吸光度。然而，通过基于未处理的对照组计算相对比率从而示出测定的吸光度值。
如图1和2所示，本发明的肽显著抑制了因VEGF而增加的血管内皮细胞的增殖。
对于血管生成，因为血管内皮细胞增殖，然后通过侵入生长和分化而形成血管，从上述结果可以看出，本发明的肽通过抑制血管内皮细胞的增殖而显著抑制血管生成。
[实验例2]抑制血管内皮细胞的分化的效果的证实
为了证实抑制血管内皮细胞的分化的效果，分别用制备例1中制备的两种肽对血管内皮细胞进行处理，然后进行小管形成试验。
具体而言，将HUVEC细胞以1.5×105个细胞/孔的密度接种在96孔板中并且孵育过夜，然后将培养基替换为无血清培养基，然后用VEGF(20ng/ml)和不同浓度的本发明的肽进行处理，并且孵育1天。但是，将2μm的舒尼替尼用作阳性对照组。在孵育完成后，使用光学显微镜目视观察管形成的测定，并且一起测定结节的数量。
如图3和4所示，证实了VEGF显著增加了血管内皮细胞的小管形成和结节数量，但本发明的肽抑制了血管内皮细胞的小管形成并且显著减少了结节数量。
[工业实用性]
本发明的用于抑制血管生成的肽以及包含所述肽作为活性成分的组合物可表现出预防或治疗由过度血管生成引起的疾病的优异效果，从而非常有效地在工业上使用，其中本发明的肽由SEQ ID NO:1或SEQ ID NO:2表示的氨基酸序列组成。
[序列表文本]
SEQ ID NO:1:Asn Lys Asn Phe Gly Tyr Asp Leu Tyr Arg
SEQ ID NO:2:Ile His Gly Thr Tyr Lys Glu Leu Leu
<110> 凯尔格恩有限公司
<120> 用于抑制血管生成的肽及其用途
<130> 2018-OPA-1058
<160> 2
<170> KoPatentIn 3.0
<210> 1
<211> 10
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 肽1
<400> 1
Asn Lys Asn Phe Gly Tyr Asp Leu Tyr Arg
1 5 10
<210> 2
<211> 9
<212> PRT
<213> 人工序列（Artificial Sequence）
<220>
<223> 肽2
<400> 2
Ile His Gly Thr Tyr Lys Glu Leu Leu
1 5
Claims (10)
1.一种用于抑制血管生成的肽，该肽包含SEQ ID NO:1或SEQ ID NO:2的氨基酸序列。
2.根据权利要求1所述的用于抑制血管生成的肽，其中所述肽的N端或C端与选自由乙酰基、芴基甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂基和聚乙二醇(PEG)组成的组中的保护基团结合。
3.根据权利要求1所述的用于抑制血管生成的肽，其中所述肽抑制血管内皮细胞的增殖、分化和迁移。
4.根据权利要求1所述的用于抑制血管生成的肽，其中所述肽与血管内皮生长因子(VEGF)受体结合。
5.根据权利要求4所述的用于抑制血管生成的肽，其中所述VEGF受体为血管内皮生长因子受体2(VEGFR2)。
6.根据权利要求1所述的用于抑制血管生成的肽，其中所述肽与VEGF竞争结合VEGF受体。
7.一种用于预防或治疗血管生成相关疾病的药物组合物，该药物组合物包含权利要求1所述的肽作为活性成分。
8.根据权利要求7的所述用于预防或治疗血管生成相关疾病的药物组合物，其中所述组合物抑制血管内皮细胞的增殖、分化和迁移。
9.根据权利要求7所述的用于预防或治疗血管生成相关疾病的药物组合物，其中所述血管生成相关疾病为选自由癌症、糖尿病性视网膜病变、早产儿视网膜病变、新生血管性青光眼、黑素瘤、增殖性视网膜病变、湿性黄斑变性、银屑病、血友病性关节炎、动脉粥样硬化斑块的毛细血管增生、瘢痕瘤、伤口肉芽、血管粘连、类风湿性关节炎、骨关节炎、自身免疫性疾病、克罗恩病、再狭窄症、动脉粥样硬化、猫抓病、溃疡、肾小球肾炎、糖尿病性肾病、恶性神经症、血栓性微血管病和肾小球病组成的组中的至少一者。
10.一种用于预防或改善血管生成相关疾病的功能性保健食品，该功能性保健食品包含权利要求1所述的肽作为活性成分。
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| US20060189519A1 (en) * | 2002-09-26 | 2006-08-24 | Karl Volz | Anti-angiogenic fragments fo pigment epithelium-derived factor (pedf) |
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| WO2013184986A2 (en) * | 2012-06-08 | 2013-12-12 | Northwestern University | Methods and compositions for inhibiting angiogenesis |
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| US20060189519A1 (en) * | 2002-09-26 | 2006-08-24 | Karl Volz | Anti-angiogenic fragments fo pigment epithelium-derived factor (pedf) |
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| EA202090811A1 (ru) | 2020-06-19 |
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| CA3075917A1 (en) | 2019-03-28 |
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| MX2020002974A (es) | 2020-10-14 |
| KR20190033873A (ko) | 2019-04-01 |
| AU2018335193A1 (en) | 2020-04-16 |
| EP3686213A4 (en) | 2020-11-18 |
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| EP3686213B1 (en) | 2022-08-17 |
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