CN102883736B - 用于促进血管生成的肽及其用途 - Google Patents
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Abstract
本发明涉及促进血管生成的肽及其用途。更具体地，本发明涉及促进血管生成的肽，以及该肽在促进血管生成以及预防或治疗血管生成相关疾病中的用途。本发明的肽对促进血管生成具有卓越的效果。因此，其对于预防或治疗血管生成相关疾病以及对于制备皮瓣的再生、创伤和烧伤愈合、人造皮肤的植入以及用于移植的血管的制备是有用的。
Description
技术领域
本申请要求2010年3月26日提交的韩国专利申请号10-2010-0027374的优先权，其在此通过引用并入。
本发明涉及用于促进血管生成的肽及其用途。更具体地，本发明涉及促进血管生成的肽，以及该肽在促进血管生成以及预防或治疗血管生成相关疾病中的用途。
背景技术
血管供给的发展是许多生理和病理过程的基本需求。生长活跃的组织如胚胎和肿瘤需要充足的血液供给。它们通过产生促血管生成因子而满足这种需要，所述促血管生成因子通过被称为血管生成的过程而促进新血管的形成。血管形成是复杂而有序的生物学事件，涉及以下步骤的全部或部分：a)由现有内皮细胞(EC)增殖出内皮细胞，或者由祖细胞分化成内皮细胞；b)EC迁移并聚集形成索样结构；c)血管索接着经过管生成过程而形成具有中央管腔的导管；d)现有的索或导管长出萌芽而形成次级导管；e)早期血管丛经过进一步重塑和整形；以及f)内皮外细胞被募集以包围内皮管，为导管提供维持和调节功能；这样的细胞包括细小毛细血管的周细胞，较大导管的平滑肌细胞，以及心脏中的心肌细胞(Hanahan,D.,Science,1997,277,48;Hogan,B.L.& Kolodziej,P.A.Nature Reviews Genetics,2002,3,513)。
血管的发育受到严格控制。目前为止，已知由外周细胞产生的大量分泌因子调控EC的分化、增殖和迁移以及聚集成索样结构。迄今已报道的促血管生成因子主要可被分成几组。它们大部分是诱导细胞生长的生长诱导因子，具有免疫活性的细胞因子、激素或脂类产物(Bussolino F et al.,Trends Biochem.Sci.,22(7),pp.251-256,1997)。
血管内皮生长因子(VEGF)已被鉴定为是参与刺激血管生成和诱导血管通透性的关键因子(Ferrara et al.,Endocr.Rev.18:4-25,1997)。已鉴定了一种鼠VEGF基因，并且分析了其在胚胎发育过程中的表达模式。在邻近内皮如脉络丛和肾脏的肾小球的矛形上皮细胞中观测到VEGF的持续表达。这些数据与VEGF作为调控EC生长和分化的多功能因子的作用相一致(Breier,G.et al.,Development,1992,114,521)。
VEGF参与所有结缔组织(例如肺脏、心脏、胎盘和实体瘤)中的血管生成(Binetruy-Tourniere et al.,EMBO J.2000,19,1525)。例如，VEGF通过刺激肿瘤相关的血管生成而参与实体瘤的生长和转移(Lu et al.,J.Biol.Chem.2003,278,43496)。此外，由于VEGF表达在结缔组织修复中是必需的，因而提出利用VEGF来修复结缔组织。
事实上，Chen等在美国专利号5,073,492(1991年12月17日)中公开了在合适的环境中协同增强内皮细胞生长的方法，其包括向环境中添加VEGF，效应物和血清来源的因子。此外，通过聚合酶链式反应技术制备了血管内皮生长因子C亚基DNA。该DNA编码可作为异型二聚体或同型二聚体存在的蛋白。该蛋白是哺乳动物血管内皮细胞有丝分裂原，并且如欧洲专利申请号92302750.2(1992年9月30日)中所述，实际上已知其具有促进血管发育和修复的用途。
尽管关于VEGF仍在发展，但是进行动物试验时，由于其较大的分子大小(与其他蛋白类似)而不能穿过血液屏障，并且由于其较短的半衰期而在短时间内被消除。虽然还在积极进行研究以发现参与血管生成的重要的EC特异性基因，并因而治疗各种血管生成相关疾病，但是目前还实质性结果。
发明内容
技术问题
本发明的发明人研究发现了可替代血管内皮生长因子(VEGF)的肽。通过合成几种新的肽，之后重复取代、添加和缺失它们的残基以及筛选有效的衍生物，本发明人合成了具有促进血管生成作用的新的肽。
本发明涉及提供了用于促进血管生成的分离的肽，其具有通式(I)或(II)所示的氨基酸序列：
(I)[N-末端–X1 X2 X3 X4 X5 X6–C-末端]
(II)[C-末端–X1 X2 X3 X4 X5 X6-N-末端]
其中X1表示不存在或为赖氨酸，X2表示不存在或为丙氨酸或谷氨酰胺，X3为甘氨酸或脯氨酸，X4表示不存在或为碱性氨基酸，X5表示酸性氨基酸，以及X6为丝氨酸。
此外，本发明涉及提供了用于促进血管生成的分离的肽，其具有通式(III)所示的氨基酸序列：
(III)[N-末端–X1 X2 X5 X6–C-末端]
其中X1为天冬酰胺，X2为谷氨酰胺，X5为酸性氨基酸，以及X6为丝氨酸。
本发明还涉及提供了用于促进血管生成的肽在制备皮瓣的再生、创伤和烧伤愈合，人造皮肤的植入以及用于移植的血管的制备中的用途。
本发明还涉及提供了所述肽在预防或治疗血管生成相关疾病中的用途，所述血管生成相关疾病选自糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血(acute posteriorischemia)，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。
技术方案
为实现以上目的，本发明提供了具有通式(I)或(II)所示的氨基酸序列的分离的肽：
(I)[N-末端X1 X2 X3 X4 X5 X6-C-末端]
(II)[C-末端-X1 X2 X3 X4 X5 X6-N-末端]
其中X1表示不存在或为赖氨酸，X2表示不存在或为丙氨酸或谷氨酰胺，X3为甘氨酸或脯氨酸，X4表示不存在或为碱性氨基酸，X5表示酸性氨基酸，以及X6为丝氨酸。
为实现另一目的，本发明提供了用于促进血管生成的分离的肽，其具有通式(III)所示的氨基酸序列：
(III)[N-末端–X1 X2 X5 X6–C-末端]
其中X1为天冬酰胺，X2为谷氨酰胺，X5为酸性氨基酸，以及X6为丝氨酸。
为实现另一目的，本发明提供了用于促进血管生成的组合物，其包含所述肽作为活性成分。
为实现另一目的，本发明提供了用于预防或治疗血管生成相关疾病的药物组合物，其包含所述肽作为活性成分，所述血管生成相关疾病选自糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。为实现又一目的，本发明提供了选自本发明肽、用作治疗剂或诊断剂的肽。
为实现再一目的，本发明提供了本发明的肽在制备促进血管生成的药剂中的用途。
为实现另一目的，本发明提供了通过给予有需要的个体有效量的本发明的肽来促进血管生成的方法。
为实现另一目的，本发明提供了本发明的肽在制备用于预防或治疗血管生成相关疾病的药剂中的用途，所述血管生成相关疾病选自糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。
为实现又一目的，本发明提供了通过给予有需要的个体有效量的本发明的肽来预防或治疗血管生成相关疾病的方法，所述血管生成相关疾病选自糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。
以下，将更详细地描述本发明。
本文所使用的氨基酸根据IUPAC-IUB命名法描述如下：
精氨酸：R， 组氨酸：H
赖氨酸：K， 天冬氨酸：D
谷氨酸：E， 丝氨酸：S
苏氨酸：T， 天冬酰胺：N
谷氨酰胺：Q， 半胱氨酸：C
甘氨酸：G， 脯氨酸：P
丙氨酸：A， 异亮氨酸：I
亮氨酸：L， 蛋氨酸：M
苯丙氨酸：F， 色氨酸：W
酪氨酸：Y， 缬氨酸V
本发明提供了用于促进血管生成的肽，其具有通式(I)或(II)所示的氨基酸序列：
(I)[N-末端–X1 X2 X3 X4 X5 X6–C-末端]
(II)[C-末端–X1 X2 X3 X4 X5 X6-N-末端]
具有通式(I)或(II)所示的氨基酸序列的肽表征如下：X1表示不存在或为赖氨酸，X2表示不存在或为丙氨酸或谷氨酰胺，X3为甘氨酸或脯氨酸，X4表示不存在或为碱性氨基酸，X5表示酸性氨基酸，以及X6为丝氨酸。
本发明的肽具有非极性氨基酸-X-酸性氨基酸-丝氨酸的基本结构，并且在非极性氨基酸和酸性氨基酸(X)之间可以具有碱性氨基酸，并且在非机械氨基酸的前面还可以包含赖氨酸和/或(丙氨酸或谷氨酰胺)添加序列(通式(I))。此外，本发明的肽可以包含所述氨基酸序列的反向序列。
本发明提供了用于促进血管生成的肽，其具有通式(III)所示的氨基酸序列：
(III)[N-末端X1 X2 X5 X6-C-末端]
具有通式(III)所示的氨基酸序列的肽表征如下：X1为天冬酰胺，X2为谷氨酰胺，X5为酸性氨基酸，以及X6为丝氨酸。
具有本发明通式(III)所示的氨基酸序列的肽具有天冬酰胺-谷氨酰胺-酸性氨基酸-丝氨酸的基本结构。
本发明首次发现了具有选自序列通式(I)至(III)这种结构的肽促进血管生成的作用。
优选地，在具有选自序列通式(I)至(III)的通式所示的氨基酸序列的肽中，所述碱性氨基酸可以是精氨酸、组氨酸或赖氨酸。所述酸性氨基酸可以是天冬氨酸或谷氨酸。
本发明的肽可以是具有选自序列通式(I)至(III)的通式所示的氨基酸序列的任何一种肽，但是优选地，其可以是具有选自SEQ ID NO.1至4的氨基酸序列的肽。
本发明的肽显示出促进血管生成的作用。其长度虽然并未被特别限定，只要其包含选自序列通式(I)至(III)的通式所示的氨基酸序列即可，但是优选地，其可以包含选自序列通式(I)至(III)的通式所示的氨基酸序列且由4至50个氨基酸组成，更优选由4至30个氨基酸组成。更优选地，其可以是具有选自序列通式(I)至(III)的通式所示的氨基酸序列的肽。最优选地，本发明的肽可以是具有选自SEQ ID NO.1至4的氨基酸序列的肽。
此外，本发明的肽可以是C-末端被酰胺化的肽。为了防止肽在体内受蛋白酶降解并增强稳定性，用各种保护基团修饰或保护N-末端和C-末端。也就是说，可以修饰肽的C-末端以提高稳定性。修饰并未被特别限定，但是优选地，可以通过羟基(-OH)或氨基(-NH2)基团来修饰。C-末端的酰胺化意味着用氨基(-NH2)基团来修饰肽的C-末端。
此外，可以修饰肽的N-末端以提高稳定性。修饰并未被特别限定，但是优选地，可以通过选自乙酰基、芴甲氧羰基(Fmoc)、甲酰基、棕榈酰基、肉豆蔻基、硬脂酰基和聚乙二醇(PEG)的基团来修饰。
本发明的肽可以根据本领域所熟知的方法来制备。例如，其可以利用自动肽合成仪来合成，或其可以通过基因改造技术来产生。例如，通过基因改造产生编码融合蛋白(包含融合伴侣和本发明的肽)的融合基因之后，用融合基因转染宿主微生物并在宿主微生物中表达融合蛋白，利用合适的蛋白酶或化合物可以从融合蛋白中切割并分离出本发明的肽。为此，可以在融合伴侣和本发明肽基因之间插入编码可被蛋白酶（如Xa因子或肠激酶)或化合物(如CNBr或羟胺)切割的氨基酸残基的DNA序列。例如，为了提供CNBr的切割位点，在要被限制性酶切割的融合伴侣的3'-末端插入包含蛋氨酸密码子具有匹配的阅读框的限制性位点(如AflIII、BsmI、BspHI、BspLU11I、NcoI、NdeI、NsiI、Ppul0I、SphI或StyI)或其同裂酶位点。并且，可以在本发明肽的基因的5'-末端插入与阅读框相连接的限制性位点，其被酶切割以连接融合伴侣和本发明肽的基因。
作为另一个实例，为了提供羟胺的切割位点，可以在融合伴侣基因和本发明肽的基因之间插入能够编码天冬酰胺-甘氨酸的DNA序列。例如，当两个基因融合时，可以在要被限制性酶切割的融合伴侣的3'-末端插入包含天冬酰胺密码子具有匹配的阅读框的限制性位点或其同裂酶位点，由此形成与酶相容的末端或平末端。并且，可以在本发明肽的基因的5'-端插入包含甘氨酸密码子并与其阅读框相连接的限制性位点，接着其被限制性酶切割以连接融合伴侣基因和本发明肽的基因。可以将本发明的基因构建体插入到常用的表达载体中，例如质粒、病毒或允许用于克隆的结构基因插入或并入宿主细胞中的媒介。
在本发明的一个实例中，利用自动肽合成仪合成具有SEQ ID NO.1至7的氨基酸序列的肽，接着通过C18反相高效液相色谱分离。
本发明的肽具有促进人或动物血管生成的作用。
本发明首次鉴定了具有本发明的氨基酸序列的肽促进血管生成的作用。
通过利用人脐静脉内皮细胞(HUVEC)的实验来验证促进血管生成作用。
在本发明的一个实例中，测试了用本发明的肽处理HUVEC是否能促进HUVEC的增殖。结果证实了用本发明的肽处理促进了HUVEC的增殖(实施例2)。
在本发明的另一个实例中，研究了本发明的肽对HUVEC迁移的作用。将本发明的肽放到具有聚碳酸酯滤膜(其下有孔)的腔室的底部并在腔室的上部添加HUVEC，孵育后对迁移到底部的细胞数进行计数并与对照组相比较。结果证实本发明的肽促进了HUVEC的迁移(实施例3)。
在本发明的又一个实例中，研究了本发明的肽对HUVEC管腔形成的作用。在平板上施加基质胶(Matrigel)并使其硬化之后，添加本发明的肽和HUVEC的混合物(在缓冲液中)，观测HUVEC在基质胶中是否形成管腔。结果证实本发明的肽促进HUVEC的管腔形成(实施例4)。
在本发明的另一个实例中，进行体内基质胶塞(Matrigel plug)分析以测定本发明的肽促进血管生成的能力。用本发明的肽和基质胶的混合物皮下注射小鼠之后，1周后取出基质胶塞并定量血管形成的程度。结果证实，与对照组相比，注射本发明的肽显示出明显更优的血管形成(实施例5)。
同样地，本发明的肽通过血管细胞的增殖、迁移和分化来促进血管生成。因此，本发明提供了用于促进血管生成的组合物，其包含本发明的肽作为活性成分。此外，本发明提供了用作治疗剂和诊断剂的肽。此外，本发明提供了本发明的肽在制备用于促进血管生成的药剂中的用途。另外，本发明提供了通过给予有需要的个体有效量的本发明的肽来促进血管生成的方法。
此外，本发明提供了用于预防或治疗血管生成相关疾病的药物组合物，其包含本发明的肽作为活性成分。另外，本发明提供了所述肽在制备用于预防或治疗血管生成相关疾病的药剂中的用途，所述血管生成相关疾病选自糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。此外，本发明提供了通过给予有需要的个体有效量的本发明的肽来预防或治疗血管生成相关疾病的方法，所述血管生成相关疾病选自糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。
本发明提供了包含本发明的肽作为有效成分的组合物，本发明的组合物可以与另一种生物活性剂如生物活性化合物、肽等组合给予。本发明的组合物还可以包含能够分化成内皮细胞(EC)的细胞。优选地，能够分化成EC的细胞可以是胚胎干细胞、间充质干细胞或造血干细胞。
优选地，用于促进血管生成的本发明的组合物可以用于皮瓣的再生、创伤和烧伤愈合，人造皮肤的植入，或者用于移植的血管的制备，但是并不限于此。血管疾病是指由于多种原因导致的血管异常引起血液或氧气供给不足而发生或恶化的疾病。优选地，非限制性示例可包括糖尿病性视网膜病变，早产儿视网膜病变，年龄相关性黄斑变性，青光眼，糖尿病足溃疡，肺高血压，缺血性心肌病，缺血性脑病，心力衰竭，急性后循环缺血，褥疮，慢性溃疡，脱发或头发变白，肥胖相关的心血管疾病以及缺血。
诸如心肌梗塞、绞痛等的心血管疾病是由血管梗阻或狭窄引起的。通过血流的氧气和营养素供给不足致使组织和器官功能异常。如果心肌发生这样的血管功能异常，心脏会停止跳动，导致心肌梗塞或绞痛。如果在手或脚末端发生，会引起缺血性肢体病。在这种情况下，病人由于极端疼痛而必须服用精神活性镇痛剂。在重度病例中，其结果为截肢或死亡。
缺血性心力衰竭是由于血管梗阻或狭窄致使血液供给减少而导致氧气不足所引起的。
糖尿病神经病变(足溃疡)是最常见的糖尿病并发症，发生于50％或更多的糖尿病患者。糖尿病患者的血管中高水平的血糖致使细胞功能异常，导致足部毛细血管和神经细胞死亡。
糖尿病视网膜病变起因于糖尿病引起的毛细血管壁的损伤(基底膜增厚，血管壁细胞减少，以及EC过度增殖)，导致毛细血管狭窄和梗阻，以及视网膜微脉管循环不足。
创伤是指皮肤组织的损伤，如外科手术切口，消化道溃疡，烧伤，撕裂和皮肤溃疡(如褥疮)。通常，创伤的治疗包括急救并等到伤口自我愈合，这需要很长的时间。一般，伤口愈合受伤口处发生的细胞增殖和新结缔组织或上皮组织形成的影响。对于伤口愈合，促进或刺激细胞的增殖和分化是有效的。
脱发是由多种原因导致的，但是已知由邻近血管向发根充足供给营养素有助于预防和逆转脱发。
上述疾病由于多种原因导致血管异常造成血液或氧气供给不足而发生或恶化，并且可以通过血管植入或血管搭桥来改善。因此，所述包含本发明的肽作为有效成分的组合物可用于血管发生或者制备用于移植的血管，以改善或治疗这些疾病。
本发明的药物组合物可单独包含本发明的肽，或者包含本发明的肽与一种或多种药学可接受的载体、赋形剂或稀释剂。可以包含药学可接受的载体，例如，用于肠胃外制剂或口服制剂的载体。用于肠胃外制剂的载体可以包括乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸。此外，用于肠胃外制剂的载体可以包括水、油、盐水、含水葡萄糖和乙二醇，以及稳定剂和防腐剂。稳定剂的实例可以是抗氧化剂，例如亚硫酸氢钠、亚硫酸钠及抗坏血酸。防腐剂的实例可以是苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯以及氯代丁醇。药学可接受载体的列表公开于《雷明顿药物科学》(Remington Pharmaceutical Sciences,第19版,Mack出版公司,Easton,PA,1995)。
本发明的药物组合物可以通过任何途径给予包括人类在内的哺乳动物。例如，其可以经肠胃外或经口给药。对于肠胃外给药，其可以通过静脉内、肌内、动脉内、骨髓内、硬膜下、心脏内、皮内、皮下、腹膜内、鼻内、胃肠道、肠胃外、舌下或直肠经肠胃外给药，但并不限于此。对于局部给药，其包括霜剂、软膏剂、凝胶和透皮贴剂，但并不限于此。
本发明的药物组合物可以被制备成如上所述的口服制剂或肠胃外制剂的形式。
对用于口服给药的配方而言，可以利用本领域已知的方法将本发明的组合物配制成粉剂、颗粒剂、片剂、丸剂和糖衣片剂、胶囊剂、液体、凝胶、糖浆、悬浮液和乳剂。例如，用于口服给药的制剂可以通过将有效组分和固体赋形剂混合、研磨并添加合适的补充剂，接着生产成颗粒混合物的形式，以片剂或糖衣片剂的形式获得。合适的赋形剂的实例可以包括：糖类，包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇和麦芽糖醇；淀粉类，包括玉米淀粉、小麦淀粉、稻米淀粉和马铃薯淀粉；纤维素类，包括纤维素、甲基纤维素、羧甲基纤维素钠和羟丙基甲基纤维素；以及填料，包括明胶和聚乙烯吡咯烷酮。此外，如果需要，其可以包含交联聚乙烯吡咯烷酮、琼脂、藻酸或藻酸钠作为溶解剂(solutionizer)。另外，本发明的药物组合物可包含抗凝剂、润滑剂、润湿剂、矫味剂、乳化剂和防腐剂。
对用于肠胃外给药的配方而言，可以利用本领域已知的方法将本发明的组合物配制成注射剂、霜剂、洗剂、软膏剂、油、润湿剂、凝胶、洗眼剂、气溶胶和鼻用吸入剂。
优选地，无菌注射剂可以是无毒且肠胃外可接受的溶剂或悬浮液中的一种。对于药学可接受的载体和媒介，有盐水、缓冲盐水、等渗盐水(例如磷酸二氢钠、磷酸氢二钠、氯化钠、氯化钾、氯化钙和氯化镁或其混合物)、林格氏溶液、葡萄糖、水、无菌水、甘油、乙醇及其混合物。优选地，作为溶剂或悬浮液介质，使用1,3-丁二醇和无菌固定油。脂肪酸如油酸也可以用于制备注射剂。
洗眼剂可以是水溶性眼用溶液，水不溶性眼用溶液或眼用乳剂。本发明的洗眼剂通过将本发明的肽溶解或悬浮于水溶性溶剂(如无菌水或盐水)或水不溶性溶剂(如棉籽油或大豆油的植物油)中制备。在这种情况下，等渗剂、pH调节剂、增稠剂、悬浮剂、乳化剂、防腐剂以及与其类似的药学可接受的添加剂。具体地，等渗剂包括氯化钠、硼酸、硝酸钠、硝酸钾、D-甘露醇和葡萄糖。增稠剂的具体实例包括硼酸、无水硫酸钠、盐酸、柠檬酸、柠檬酸钠、硝酸、乙酸钾、碳酸钠以及硼砂。pH调节剂的具体实例包括甲基纤维素、羟丙基甲基纤维素、聚乙烯醇、硫酸软骨素钠以及聚乙烯吡咯烷酮。悬浮剂的具体实例包括聚山梨酯80和聚氧乙烯以及氢化蓖麻油。乳化剂的具体实例包括蛋黄卵磷脂和聚山梨酯80，但不限于此。防腐剂的具体实例包括苯扎氯铵、苄索氯铵、氯丁醇、苯乙醇以及对羟基苯甲酸酯，但不限于此。配方公布于《雷明顿药物科学》(第15版，1975，Mack Publishing Company,East on,Pennsylvania 18042,87章:Blaug,Seymour)。
优选地，本发明的药物组合物可包含0.001-99.999重量百分比和99.999-0.0001重量百分比的药学可接受的载体。
如本文所使用，术语量是指向有需要的个体递送的药物的量，或者对促进血管生成显示起作用的量以及对预防或治疗个体中血管生成相关疾病有作用的量，并且涉及哺乳动物，优选涉及包括人在内的哺乳动物，其可以是源自动物的细胞、器官和组织。个体可以是需要治疗疾病的病人。
本发明组合物的总的有效量可以以单剂量给予病人，或者可以通过分次治疗方案以多剂量给予。根据疾病严重程度，本发明的药物组合物可包含不同量的有效成分。优选地，本发明肽的总量是约0.0001μg至500mg/kg体重/日，最优选地，其可以是0.01μg至l00mg/kg体重/日。然而，所述肽的剂量可以通过考虑多种因素而适当地确定，例如需要治疗的个体的年龄、体重、健康状况、性别，疾病严重程度、饮食和排泄，以及给药时间和给药途径。因而，这些都被考虑时，本领域技术人员可确定用于特定用途的组合物的合适剂量。本发明的药物组合物可不限定制剂、给药途径和给药方法，只要它们能显示本发明的效果即可。
有益效果
由上述可见，本发明提供了新的肽，用于促进血管生成的包含该肽作为活性成分的组合物。本发明的肽对促进血管生成具有卓越的效果，本发明的药物组合物促进血管生成的作用优于VEGF，并且由于其分子量更低，与VEGF相比更容易渗透入血管和组织。因此，包含所述肽的组合物对于预防和/或治疗血管生成相关疾病和对于制备皮瓣的再生、创伤和烧伤愈合，人造皮肤的植入以及用于移植的血管的制备是有用的。
附图说明
图1比较了本发明的肽对促进内皮细胞(EC)增殖的作用(No：阴性对照，VEGF：阳性对照，Pep_7至10：SEQ ID NO.1至4的肽)；
图2比较了本发明的肽对促进内皮细胞(EC)迁移的作用(No：阴性对照，VEGF：阳性对照，Pep_7至10：SEQ ID NO.1至4的肽)；以及
图3显示了由本发明的肽促进的EC管腔形成的摄影图片(No：阴性对照，VEGF：阳性对照，Pep_7至10：SEQ ID NO.1至4的肽)。
实施方式
以下，将通过实施例详细描述本发明。然而，应当理解的是，这些实施例仅是说明的目的，并不应当解释为对本发明范围的限制。
实施例1肽的制备
具有表1中所示的氨基酸序列的肽利用自动肽合成仪(Milligen 9050,Millipore,USA)合成，接着通过C18反相高效液相色谱(HPLC)(WatersAssociates,USA)完全分离。使用了ACQUITY UPLC BEH300 C18柱(2.1x100mm,1.7um,Waters Co,USA)。
表1所制备的肽的氨基酸序列
| SEQ ID NO. | 肽名称 | 序列 |
| 1 | Pep_7 | SEGQK |
| 2 | Pep_8 | SDRGA |
| 3 | Pep_9 | PKES |
| 4 | Pep_10 | NQES |
实施例2对HUVEC增殖的作用
为了研究实施例1中制备的4种肽对血管形成的作用，用本发明的肽处理人脐静脉内皮细胞(HUVEC)并观测它们的增殖。
在含2％胎牛血清(FBS)的内皮细胞基础培养基-2(EBM-2,CloneticsCo.,San Diego,USA)中培养HUVEC。将所培养的HUVEC以每孔1000细胞转移到96-孔板。培养24小时之后，向每个孔添加本发明的4种肽，再进一步培养48小时。在相同条件下培养用VEGF代替本发明的肽处理的细胞和未经任何处理的细胞分别作为阳性对照组和阴性对照组。培养结束时，利用CyQUANT试剂盒(Invitrogen,USA)测定细胞增殖的程度。
由表2和图1可见，本发明的肽表现出促进HUVEC增殖的优越作用。一些肽甚至显示出优于阳性对照VEGF的结果。
表2促进细胞增殖的作用
| 肽/对照组 | 细胞增殖(％) |
| 阴性对照(未处理的) | 100 |
| 阳性对照(VEGF) | 166.0 |
| Pep_7 | 203.3 |
| Pep_8 | 209.2 |
| Pep_9 | 212.5 |
| Pep_10 | 146.5 |
实施例3对HUVEC迁移的作用
为了研究实施例1中制备的4种肽对血管形成的作用，测定HUVEC的迁移。
用0.5mg/mL I型胶原蛋白(10mL)包被具有聚碳酸酯滤膜(其下有孔)的24-孔板(Corning Costar,USA)的腔室底部。将含有本发明的4种肽的EBM-2添加到腔室底部之后，在腔室的上部以每孔1x105细胞接种HUVEC。于37°C孵育10小时之后，将穿过聚碳酸酯滤膜的细胞用甲醇固定，用苏木精染色并用显微镜计数。
由表3和图2可见，本发明的肽促进HUVEC的迁移。一些肽甚至显示出优于阳性对照VEGF的结果。
表3促进细胞迁移的作用
| 肽/对照组 | 细胞迁移(％) |
| 阴性对照(未处理的) | 100 |
| 阳性对照(VEGF) | 146.3 |
| Pep_7 | 155.4 |
| Pep_8 | 147.0 |
| Pep_9 | 156.4 |
| Pep_10 | 173.2 |
实施例4对促进HUVEC管腔形成的作用
研究了本发明的肽对HUVEC管腔形成的作用。
在含2％FBS的EGM-2中培养HUVEC，接着在不含FBS的培养基中饥饿12小时。将基质胶(BD Biosciences,USA)以每孔150μＬ均匀施加于24孔板上并使其硬化，小心以防止起泡。在用含1％FBS的培养基将细胞悬浮于本发明的肽的混合物中之后，以每孔1X105细胞接种细胞，并于37°C下孵育。18小时之后，用显微镜观测HUVEC是否形成管腔。
由图3可见，证实了本发明的肽促进HUVEC的管腔形成。
实施例5对促进血管形成的作用
通过体内基质胶塞分析研究本发明的肽促进血管生成的能力。
用600μL每一种本发明的肽和减少生长因子的基质胶(BDBiosciences,USA)的混合物皮下注射7周龄雄性C57BL/6小鼠。用已知诱导血管生成的VEGF(R&D Systems,USA)注射小鼠，作为阳性对照。一周之后，将小鼠处死并取出硬化的基质胶塞，定量血管形成的程度。利用Drabkin's试剂盒(Sigma,USA)通过测定血红蛋白的量来进行定量。
结果证实，本发明肽的注射与对照组相比显示出明显更优的血管生成。
工业应用
本发明的新肽对促进血管生成具有卓越的作用。本发明的肽促进血管生成的作用优于VEGF，并且由于更低的分子量，其与VEGF相比更易于渗透入血管和组织。因此，包含该肽的组合物对于预防和/或治疗血管生成相关疾病以及对于制备皮瓣的再生、创伤和烧伤愈合，人造皮肤的植入以及用于移植的血管的制备是有用的。
Claims (9)
1.分离的肽，其由SEQ ID NO:2所示的氨基酸序列组成。
2.如权利要求1所述的分离的肽，其中所述肽在其C-末端处被酰胺化。
3.用于促进血管生成的组合物，其包含权利要求1或2所述的肽作为活性成分。
4.如权利要求3所述的组合物，其中所述组合物用于皮瓣的再生、创伤和烧伤愈合、人造皮肤的植入或用于移植的血管的制备。
5.用于预防或治疗缺血性心肌病的药物组合物，其包含权利要求1或2所述的肽作为活性成分。
6.用作治疗剂或诊断剂的权利要求1或2所述的分离的肽。
7.权利要求1或2所述的肽在制备用于促进血管生成的药物中的用途。
8.权利要求1或2所述的肽在制备用于预防或治疗缺血性心肌病的药物中的用途。
9.包含权利要求1或2所述的肽的组合物。
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410332373.9A CN104072584B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
| CN201410332375.8A CN104072580B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
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| KR1020100027374A KR101335203B1 (ko) | 2010-03-26 | 2010-03-26 | 혈관신생촉진용 펩타이드 및 이의 용도 |
| KR10-2010-0027374 | 2010-03-26 | ||
| PCT/KR2011/002081 WO2011119009A2 (en) | 2010-03-26 | 2011-03-25 | Peptides for promoting angiogenesis and an use thereof |
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| CN201410332373.9A Division CN104072584B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
| CN201410332375.8A Division CN104072580B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
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| CN102883736A CN102883736A (zh) | 2013-01-16 |
| CN102883736B true CN102883736B (zh) | 2014-08-13 |
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| CN201180021591.5A Expired - Fee Related CN102883736B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
| CN201410332373.9A Expired - Fee Related CN104072584B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
| CN201410332375.8A Expired - Fee Related CN104072580B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
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| CN201410332373.9A Expired - Fee Related CN104072584B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
| CN201410332375.8A Expired - Fee Related CN104072580B (zh) | 2010-03-26 | 2011-03-25 | 用于促进血管生成的肽及其用途 |
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| US (2) | US9610318B2 (zh) |
| EP (3) | EP3085379A1 (zh) |
| JP (1) | JP5701375B2 (zh) |
| KR (1) | KR101335203B1 (zh) |
| CN (3) | CN102883736B (zh) |
| WO (1) | WO2011119009A2 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2013067488A1 (en) | 2011-11-05 | 2013-05-10 | Massachusetts Institute Of Technology | Method and apparatus for efficient transmission of information to multiple nodes |
| KR102494803B1 (ko) * | 2013-11-22 | 2023-02-06 | 주식회사 젬백스앤카엘 | 혈관 신생 억제 활성을 가지는 펩티드 및 이를 포함하는 조성물 |
| US10183055B2 (en) | 2014-07-21 | 2019-01-22 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Ang-(1-7) derivative oligopeptides for the treatment of pain and other indications |
| WO2016014342A2 (en) | 2014-07-21 | 2016-01-28 | Arizona Board Of Regents For The University Of Arizona | Ang-(1-7) derviative oligopeptides and methods for using and producing the same |
| WO2016068217A1 (ja) * | 2014-10-29 | 2016-05-06 | 国立大学法人山口大学 | 末梢血単核球又は末梢血単核球より分泌される因子を伴う線維芽細胞を含む細胞シート |
| CN106046146A (zh) * | 2016-06-07 | 2016-10-26 | 南京医科大学附属脑科医院 | 一种血管生成激动剂多肽及应用 |
| CN105968187A (zh) * | 2016-06-07 | 2016-09-28 | 南京医科大学附属脑科医院 | 一种血管生成激动剂多肽及应用 |
| KR20200016226A (ko) * | 2017-05-30 | 2020-02-14 | 가부시키가이샤 아데카 | 이식용 탈세포화 재료의 제조 방법 및 당해 재료를 포함하는 생체 적합성 재료로 이루어지는 이식편 조성물 |
| KR101998155B1 (ko) | 2017-09-22 | 2019-07-10 | (주)케어젠 | 혈관신생 억제용 펩타이드 및 이의 용도 |
| US20220105157A1 (en) * | 2019-01-04 | 2022-04-07 | The Regents Of The University Of California | Compositions and Methods for Promoting Angiogenesis in the Eye |
| TWI754324B (zh) * | 2020-07-16 | 2022-02-01 | 三凡生技研發股份有限公司 | 促進血管增生之短鏈胜肽組合物及其於糖尿病傷口癒合之用途 |
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- 2011-03-25 CN CN201180021591.5A patent/CN102883736B/zh not_active Expired - Fee Related
- 2011-03-25 EP EP16171437.3A patent/EP3085379A1/en not_active Withdrawn
- 2011-03-25 EP EP11759758.3A patent/EP2552470B1/en not_active Not-in-force
- 2011-03-25 EP EP16171438.1A patent/EP3087994A1/en not_active Withdrawn
- 2011-03-25 CN CN201410332373.9A patent/CN104072584B/zh not_active Expired - Fee Related
- 2011-03-25 WO PCT/KR2011/002081 patent/WO2011119009A2/en active Application Filing
- 2011-03-25 US US13/637,602 patent/US9610318B2/en not_active Expired - Fee Related
- 2011-03-25 CN CN201410332375.8A patent/CN104072580B/zh not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| CN104072580B (zh) | 2017-01-04 |
| CN104072580A (zh) | 2014-10-01 |
| EP2552470A4 (en) | 2014-02-19 |
| WO2011119009A2 (en) | 2011-09-29 |
| JP2013523720A (ja) | 2013-06-17 |
| KR20110108080A (ko) | 2011-10-05 |
| CN102883736A (zh) | 2013-01-16 |
| EP2552470A2 (en) | 2013-02-06 |
| KR101335203B1 (ko) | 2013-11-29 |
| US20170166609A1 (en) | 2017-06-15 |
| CN104072584A (zh) | 2014-10-01 |
| EP3087994A1 (en) | 2016-11-02 |
| CN104072584B (zh) | 2017-04-26 |
| JP5701375B2 (ja) | 2015-04-15 |
| US20130137637A1 (en) | 2013-05-30 |
| WO2011119009A3 (en) | 2012-04-05 |
| EP3085379A1 (en) | 2016-10-26 |
| US9938320B2 (en) | 2018-04-10 |
| EP2552470B1 (en) | 2016-09-07 |
| US9610318B2 (en) | 2017-04-04 |
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