CN102348716A - 头蛋白-来源的肽及其用途 - Google Patents
头蛋白-来源的肽及其用途 Download PDFInfo
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- CN102348716A CN102348716A CN2009801579080A CN200980157908A CN102348716A CN 102348716 A CN102348716 A CN 102348716A CN 2009801579080 A CN2009801579080 A CN 2009801579080A CN 200980157908 A CN200980157908 A CN 200980157908A CN 102348716 A CN102348716 A CN 102348716A
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Abstract
本发明公开了用于促进毛发生长,改良皮肤状态,提供抗炎症功能,或预防或治疗骨疾病的头蛋白-来源的肽和含所述肽的组合物。本发明公开的头蛋白-来源的肽发挥相同或类似于天然的人头蛋白的功能且在稳定性和皮肤通透性上更优。含本发明的肽作为活性成分的组合物在治疗,预防或改善生长因子-相关的症状(例如脱发,皮肤病情或创伤)或治疗,预防或改善生长因子过表达-相关的症状中呈现显著优秀的效应。因此,本发明的肽的优秀的活性和稳定性在应用于医学,准药品及化妆品中大大有利。
Description
【技术领域】
本发明涉及头蛋白(noggin)-来源的肽和含所述肽的组合物。
【背景技术】
毛囊是哺乳动物特有的皮肤器官。毛囊的基部是称为乳突的大的结构(Stenn and Paus,Physiol.Rev.,81:449(2002))。乳突在毛囊的正常循环及毛干生长中必要(Oliver,Embryol.Exp.Morph.15:331(1966);Oliver,Embryol.Exp.Morph.16:231(1967))。毛干是由上皮细胞组成的线形结构,其包含角蛋白丝及紧密附接其上的丝-聚集蛋白。
人毛遵循具有3不同的期的生长循环:生长期,退化期及休止期。毛发生长循环被激素或许多生长因子调节。严重的应激或营养不良可发展到退化期及休止期期,导致严重的脱发(alopecia)(Vladimir A.Botchkarev,American Journal of Pathology,162(3):709-712(2003))。
在男子型脱发中,在头皮的前部及顶部的毛囊敏感于雄激素,其导致毛囊缩小,由此导致脱发。在20%的女性中,在头皮顶部毛常变得更薄,导致“女子型脱发”。脱发随着年老而扩散。而且,由损伤,疾病或燃烧所致的瘢痕性脱发可导致严重的脱发。无论何种原因,脱发可具有显著的心理学,社会及性影响,以及伤害自尊心。尽管各药物已用于治疗脱发,但它们太昂贵,或在个体中给出非常不同的结果。
在化妆产物中,使用了廉价但欠有效的植物提取物,其不给出良好的结果。为克服这些问题,通过使用大肠埃希氏菌(E.coli)发酵和纯化而大规模产生源于人的角质形成细胞生长因子,并且开发纳米体技术来改善皮肤通透性。而且,通过添加角质形成细胞生长因子-来源的肽进一步改善效应。角质形成细胞生长因子辅助毛产生和生长的生长期。其保持生长期的毛循环,由此减少由各环境因素所致的脱发,且在正常毛中,其通过供给营养贡献于毛的生长和健康。脱发的治疗和解决方案经时间发生大的变化。尽管脱发可使用假发或男用假发或通过扩展毛发覆盖,但它们无法导致毛再生长。并且,尽管2种目前可用的药物(米诺地尔和非那雄胺)已知可延缓进一步脱发,但它们不诱导毛囊再生。许多使用植物提取物的用于防止脱发的毛发护理化妆品已投入到市场。尤其开发了,使用槐树,辣椒,胡椒,桑树根,桑树叶,人参,甘草,牡丹,毛地黄,小茴香,日本山茱萸,大蒜,等的提取物的产品,用于改善被过量的二氢睾酮(DHT)抑制的细胞代谢及以通过添加含黄嘌呤和生长激素的组合物辅助毛再生和生长的产品,用于将营养供给到头皮及毛,及通过添加矿物,维生素和绿茶,迷迭香,艾蒿及甘草的提取物阻止脱发和促进毛发生长的产品,及用于通过抑制5-α还原酶来抑制雄激素代谢期间DHT的产生,且以通过将物质(例如维生素B,维生素C,维生素D,维生素E,烟酸,泛酸,生物素,叶酸,等)与植物提取物混合来辅助毛代谢的男子型脱发产品。但它们难以影响新毛发产生。而且,已通过使用,例如,由日本东京的Jikei University School of Medicine的一个研究小组显示在糖尿病中有效的科罗索酸等开发了抑制5-α还原酶和呈现优良的毛发生长效应的产品。
许多因子涉及毛发的生长及脱落。本发明的发明人已通过活化角质形成细胞生长因子和血管内皮生长因子和抑制BMP蛋白的活性来研究了促进毛发产生和生长的生长因子。尤其是,已通过使用大肠埃希氏菌(E.coli)发酵和纯化大规模产生了头蛋白,其抑制BMP2/4,其抑制人-来源的角质形成细胞生长因子FGF-7(KGF);和FGF-10,其涉及毛发循环及在毛囊生长期间延缓生长期的起始,并且将它们开发成含生长因子的化妆品来促进毛发生长和阻止脱发(韩国专利No.1007968170000;Growth factor for hair and skin treatment)。尽管生长因子提供优良效果,需要用于再折叠的额外的加工和时间来获得野生型生长因子。而且,复杂的纯化处理对于去除源于大肠埃希氏菌(E.coli)的污染源是必需的,且稳定性和高分子量问题以及高成本使其不太好应用。
为了解决与生长因子表达相关的问题,已企图通过固相合成仅产生一些生长因子的一部分,以达到类似功能。例如,在美国专利No.5,473,054,Jameson等人分别将IGF-1的29~38和61~70片段命名为JB2和JB1,并报告了肽片段对细胞生长的效应以及JB3(JB1的对映体)针对IGF-1的抑制性效应。而且,Teruo等人已在WO 03/048192中报告了IGF-1的33~37片段和物质P-来源的四肽在创伤治愈中的互补作用。此外,Kodama等人已在Autoimmunity 37:481-487(2004)中报告了IGF-1的50~70片段辅助治疗小鼠中的糖尿病。
说明书通篇引用了许多出版物和专利文献。将所引用的出版物和专利文献的公开内容其通过引用整体并入本文,以更明确说明现有技术及本发明的状态。
【发明内容】
本发明的发明人制备和筛选出各种源于人头蛋白的肽,以便制备在稳定性和皮肤通透性上相对天然的生长因子头蛋白优秀,且发挥相同或类似于天然的头蛋白的功能的肽。结果,他们在许多候选肽之中筛选出提供优秀的生理活性以及优秀的稳定性和皮肤通透性的肽。
本发明针对提供呈现生长因子活性的肽。
本发明也针对提供用于促进毛发生长的组合物。
本发明也针对提供用于改善皮肤状态的组合物。
本发明也针对提供抗炎症组合物。
本发明也针对提供用于预防或治疗骨疾病的组合物。
其他特征和方面将从以下详述,附图和权利要求中显而易见。
在一个总的方面,本发明提供呈现生长因子活性的肽,包括由通式1表示的氨基酸序列:
【通式1】
Glu-Leu-Ile-Glu-His-接头-Arg-Pro-Ala-Asp
在另一个总的方面,本发明提供用于促进毛发生长的组合物,其含呈现生长因子活性的肽作为活性成分。
在另一个总的方面,本发明提供用于改善皮肤状态的组合物,其含呈现生长因子活性的肽作为活性成分。
在另一个总的方面,本发明提供抗炎症组合物,其含呈现生长因子活性的肽作为活性成分。
在另一个总的方面,本发明提供用于预防或治疗骨疾病的组合物,其含呈现生长因子活性的肽作为活性成分。
本发明的发明人制备和筛选出各种源于人头蛋白的肽,以便制备在稳定性和皮肤通透性上优于天然的生长因子头蛋白,且发挥相同或类似于天然的头蛋白的功能的肽。结果,他们在许多候选肽之中筛选出提供优秀的生理活性以及优秀的稳定性和皮肤通透性的肽。
本发明的发明人随机合成了生长因子头蛋白的几个部分,并探究了能与受体蛋白结合的位点。然后,通过优化期望的部分的氨基酸序列,制备出候选体肽,在其中筛选出呈现最佳活性的肽作为本发明的肽。
本发明的肽包括通式1表示的氨基酸序列。特别是,本发明的肽基本上由通式1表示的氨基酸序列构成。更特别地,本发明的肽由通式1表示的氨基酸序列构成。
在通式1表示的氨基酸序列中,头蛋白-来源的序列在N-及C-末端通过接头连接。
本发明中使用的接头可为本领域通常使用的那些。接头可具有特别选定的长度和/或序列,以最大化本发明肽的活性,即头蛋白活性。
特别是,接头可包括多个氨基酸残基。包括氨基酸序列的接头描述于Huston,et al.,Methods in Enzymology,203:46-88(1991)和Whitlow,et al.,Protein Eng.,6:989(1993),将其通过引用并入本文。适宜于本发明的接头主要包括甘氨酸,或甘氨酸和丝氨酸氨基酸残基,且为2~18个氨基酸长。在本发明的特定实施方式中,接头包括多个氨基酸残基。在本发明的更特定的实施方式中,接头包括2~10个Gly残基,更特别地2~7个Gly残基,更特别地3个Gly残基。
本发明的肽相比天然的头蛋白具有更佳稳定性,但其稳定性可通过氨基酸修饰进一步改善。
在本发明的特定实施方式中,肽的N-末端或C-末端可结合到保护基,其选自:乙酰基,芴基甲氧基羰基,甲酰基,棕榈酰基,肉豆蔻基,硬脂酰基,聚乙二醇(PEG)和氨基酸。
在本发明的特定实施方式中,肽的C-末端可用羟基(-OH)或氨基(-NH2)修饰。
本发明的肽的稳定性可通过氨基酸修饰大大改善。如本文所用,术语“稳定性”不仅指体内稳定性而且指储存稳定性(例如,于室温的储存稳定性)。保护基从蛋白水解酶的攻击保护本发明的肽。
如本文所用,术语“肽”指线性-链分子,其中氨基酸残基通过肽键连接。本发明的肽可根据已知的化学合成技术,尤其固相合成技术制备(Merrifield,J.Amer.Chem.Soc.85:2149-54(1963);Stewart,et al.,Solid Phase Peptide Synthesis,2nd.ed.,Pierce Chem.Co.:Rockford,111(1984))。
本发明的肽具有相同或类似于天然的生长因子头蛋白的活性。
在本发明的特定实施方式中,本发明的肽具有促进细胞生长的能力。在本发明的特定实施方式中,本发明的肽促进层粘连蛋白或透明质酸的产生。
在本发明的特定实施方式中,本发明的肽通过与骨形态生成蛋白(BMP)-2,BMP-4或BMP-7结合而呈现针对BMP-2,BMP-4或BMP-7的拮抗剂活性。就是说,本发明的肽通过强烈结合到BMP-2,BMP-4和/或BMP-7和由此防止它们与它们的受体结合来呈现拮抗剂活性。
更特别是,本发明的肽呈现对于涉及BMP-2,BMP-4或BMP-7的疾病,病症或病情的预防或治疗效果,且所述疾病,病症或病情是脱发,炎症或骨疾病。
如本文所用,术语“涉及BMP-2,BMP-4或BMP-7的疾病,病症或病情”指由BMP-2,BMP-4或BMP-7的过表达所致的病理状态。
本领域熟知,BMP-2,BMP-4和BMP-7涉及各种病理状态,例如脱发,炎症或骨疾病(Kanami I,et al.,Bone Morphogenetic Protein2 Stimulates Osteoclast Differentiation and Survival Supported byReceptor Activator of Nuclear Factor-κB Ligand,Endocrinology,142(8):3656-662(2001);US专利申请No.20060276385;and WO99/61044)。因此,呈现针对BMP-2,BMP-4或BMP-7的拮抗剂活性的本发明的肽在预防或治疗涉及BMP-2,BMP-4或BMP-7的疾病中有效。
在另一个总的方面,本发明提供用于促进毛发生长的组合物,其包括呈现生长因子活性的肽作为活性成分。
头蛋白是通过结合到TGF-β家族配体来抑制转化生长因子(TGF-β)信号转导的多肽。如其他TGF-β抑制剂(例如脊索发生素或卵泡抑素),头蛋白抑制毛囊中表达的BMP活性,尤其BMP-2,BMP-4和BMP-7活性(American Journal of Path.,Vol.165,No.3:729-740(2004))。
在本发明的实施方式中,本发明的肽源于人头蛋白,且在动物实验中大大增强毛发生长(图10)。
如本文所用,术语“促进毛发生长”和“防止脱发”作为同义词使用。
在本发明的特定实施方式中,通过本发明的组合物预防或治疗的脱发包括斑秃,全秃,普秃,雄激素性脱发(男子型脱发),休止期脱发,生长期脱发或化学治疗-诱导的脱发,但不限于这些(Cotsareliset al.,Towards a molecular understanding of hair loss and itstreatment,Trends in Mol.Med.,7:293-301(2001);MacDonald,N.,Alopecia areata:identification and current treatment approaches,Dermatol.Nurs.,11:356-359(1999))。
在另一个总的方面,本发明提供用于改善皮肤状态的组合物,其包括呈现生长因子活性的肽作为活性成分。
在本发明的特定实施方式中,皮肤状态的改善包括:皱纹改善,皮肤弹性改善,防止皮肤老化,改善皮肤保湿,去除老年斑,或治愈创伤。如在后述实施例展示,本发明的肽可通过辅助角质形成细胞和成纤维细胞增殖和促进层粘连蛋白和透明质酸产生来改善各种皮肤状态。
在另一个总的方面,本发明提供用于预防或治疗涉及BMP-2,BMP-4或BMP-7的疾病,病症或病情的组合物,其包括抑制BMP活性的肽作为活性成分。
本发明的肽通过结合到BMP-2,BMP-4和BMP-7而呈现针对BMP蛋白,尤其BMP-2,BMP-4和BMP-7的拮抗剂活性。
在本发明的特定实施方式中,通过本发明的肽的拮抗剂活性预防或治疗的疾病,病症或病情是炎症或骨疾病。
各炎症疾病可通过本发明的肽预防或治疗。非-限制例包括:脑炎,炎性肠病,慢性阻塞性肺部疾病,过敏,脓毒性休克,肺部纤维化,未分化的脊椎关节病,未分化的关节病,关节炎,炎症骨质溶解,及由病毒或细菌感染所致的慢性发炎。
各种骨疾病可通过本发明的肽预防或治疗。非-限制例包括:骨关节炎,类风湿性关节炎,由癌细胞骨转移所致的骨损伤,骨质疏松症,骨软化症,佝偻病,纤维性骨炎,再生障碍性骨疾病,代谢骨疾病,骨质溶解,白细胞减少,骨畸形,高钙血症或神经压缩综合征。
由于本发明的组合物包括上述本发明的头蛋白-来源的肽作为活性成分,将不再次给予详述。
在本发明的特定实施方式中,本发明的组合物是药物组合物,其包括:(a)本发明的上述药学有效量的头蛋白-来源的肽;及(b)药学可接受的载质。
如本文所用,术语“药学有效量”指足以达到上述头蛋白-来源的肽的效应或活性的量。
本发明的药物组合物中包括的药学可接受的载质可为本领域通常采用的。非-限制例包括:乳糖,右旋糖,蔗糖,山梨糖醇,甘露糖醇,淀粉,胶阿拉伯胶,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,矿油,等。本发明的药物组合物除了上述成分之外,可还包括,润滑剂,润湿剂,甜味剂,芳香,乳化剂,悬浮剂,防腐剂等。适宜药学可接受的载质和制剂详细描述于Remington′s Pharmaceutical Sciences(19th ed.,1995)。
本发明的药物组合物可经口或肠胃外施用。对于肠胃外施用而言,其可静脉内,经皮下,肌内,腹内,透皮,等施用。
本发明的药物组合物的适当的剂量可取决于各种因素,如制备方法,施用方法,患者的年龄,体重和性别,病理状态,摄食,施用时间,施用途径,排泄速度或应答灵敏度来测定。本发明的药物组合物的建议的剂量是0.0001~100μg/天。
本发明的药物组合物可根据本领域技术人员容易采用的方法可制备成单元剂型或多个剂型,以及药学可接受的载质和/或赋形剂。制剂可为油包溶液或含水介质,悬浮液,乳液,提取物,粉末,颗粒剂,片剂,胶囊或凝胶(例如,水凝胶)形式,且还可包括分散剂或稳定剂。
在本发明的特定实施方式中,本发明的组合物是化妆组合物,其包括:(a)化妆有效量的本发明的上述头蛋白-来源的肽;及(b)药学可接受的载质。
如本文所用,术语“化妆有效量”指足以达到皮肤状态改善的本发明的组合物的量。
本发明的化妆组合物可配制成本领域中通常使用的任何形式。非-限制例包括:溶液,悬浮液,乳液,糊剂,凝胶,霜,洗液,粉末,肥皂,含表面活性剂的清洁剂,油,粉底,乳液底,蜡底,喷雾剂,等。更特别是,其可制备成润肤液,营养洗液,营养霜,按摩霜,精华液,眼霜,清洁霜,清洁沫,清洁水,包裹(pack),喷雾剂或粉末。
当本发明的组合物为糊剂,霜或凝胶形式时,可将动物油,植物油,蜡,石蜡,淀粉,黄蓍胶,纤维素衍生物,聚乙二醇,硅酮,膨润土,氧化硅,滑石粉,氧化锌,等用作载质。
当本发明的组合物为粉末或喷雾形式时,可将乳糖,滑石粉,氧化硅,氢氧化铝,硅酸钙或聚酰胺粉末用作载质。尤其,喷雾可还包括推进剂,例如氢氯氟碳,丙烷/丁烷或二甲基醚。
当本发明的组合物为溶液或乳液形式时,可将溶剂,增溶剂或乳化剂用作载质,例包括:水,乙醇,异丙醇,碳酸乙酯,乙酸乙酯,苄基醇,苯甲酸苄酯,丙二醇,1,3-丁二醇油,甘油脂肪族酯,聚乙二醇或山梨糖醇酐脂肪酸酯。
当本发明的组合物为悬浮液形式时,可将液体稀释剂,例如水,乙醇或丙二醇,悬浮液,例如乙氧基化的异硬脂醇,聚氧乙烯山梨糖醇酯和聚氧乙烯山梨糖醇酐酯,微晶纤维素,间氢氧化铝,膨润土,琼脂,黄蓍胶,等用作载质。
当本发明的组合物为含表面活性剂的清洁剂形式时,可将脂肪族醇硫酸酯,脂肪族醇醚硫酸酯,硫代琥珀酸单酯,羟乙磺酸酯,咪唑啉鎓衍生物,牛磺酸甲酯,肌氨酸酯,脂肪酸酰胺醚硫酸盐,烷基酰胺甜菜碱,脂肪族醇,脂肪酸甘油酯,脂肪酸二乙醇胺,植物油,羊毛脂衍生物,乙氧基化的甘油脂肪酸酯,等用作载质。
除了作为活性成分的肽和载质成分之外,本发明的化妆组合物可还包括化妆组合物中通常使用的那些成分。例包括:常见的辅佐剂,例如抗氧化剂,稳定剂,增溶剂,维生素,色素和芳香剂。
本发明的特征和优势可总结如下:
(a)本发明的头蛋白-来源的肽可发挥相同或类似于天然的人头蛋白的功能。
(b)本发明的肽相比天然的头蛋白提供更佳稳定性,且呈现优良的皮肤通透性。
(c)包括本发明的肽作为活性成分的组合物在治疗,预防或改善生长因子-相关的症状,例如脱发,皮肤病情或创伤中,或治疗,预防或改善生长因子过表达-相关的症状中非常有效。
(d)本发明的肽的优秀的活性和稳定性在医学,准药品及化妆品应用中大大有利。
【附图说明】
图1显示根据本发明合成的肽的高效液相色谱法分析结果。
图2a显示用根据本发明合成的肽处理的角质形成细胞的细胞生长速率。
图2b显示用根据本发明合成的肽处理的成纤维细胞的细胞生长速率。
图3是显示用本发明的肽处理的角质形成细胞和成纤维细胞中的细胞生长促进效应的显微镜图像。
图4a显示用本发明的肽处理的成纤维细胞中层粘连蛋白的增加的产生。
图4b显示用本发明的肽处理的成纤维细胞中透明质酸的增加的产生。
图5显示比较由用根据本发明制备的肽处理后,用α-MSH处理的B16黑色素瘤细胞的黑色素产生的结果。
图6显示UV辐射后,用α-MSH处理的B16黑色素瘤细胞的黑色素产生。
图7显示用于鉴定根据本发明制备的肽与BMP-4蛋白的结合能力的Biacore测试结果。
图8a显示用于鉴定根据本发明制备的肽与BMP-4蛋白的结合能力的SDS-PAGE结果。洗脱1,洗脱2和洗脱3是依次通过用0.5M NaCl和50mM磷酸铵(pH4.0)溶液洗脱得到的级分。尺寸标记物(SM)的蛋白尺寸是100,70,50,40,30,20和15kDa。
图8b显示用于鉴定根据本发明制备的肽与BMP-4蛋白的结合能力的蛋白印迹。在右侧的标准蛋白同于在图8a中的洗脱级分。
图9比较本发明的肽的热稳定性。
图10显示对用本发明的肽处理的小鼠背部皮肤的毛发生长促进效应。
【实施例】
以下描述实施例和实验。以下实施例和实验仅旨在阐明,且不期望限制本发明的范围。
【合成例:Glu-Leu-Ile-Glu-His-接头-Arg-Pro-Ala-Asp的合成(SEQ ID NO:1)】
将700mg的氯三苯甲基氯(CTL)树脂(Nova Biochem,Cat No.01-64-0021)放入反应器及在添加10mL的二氯甲烷(MC)后搅拌3分钟。去除溶剂后,添加10mL的二甲基甲酰胺(DMF)。然后,搅拌3分钟后,再次去除溶剂。将10mL的二氯甲烷(DCM)添加到反应器后,添加200mmol的Fmoc-Asp(tBu)-OH(Bachem,Swiss)和400mmol的二异丙基乙胺(DIEA),并通过搅拌良好溶解。搅拌着反应1小时后,将混合物用甲醇和DIEA(2∶1)在DCM中洗涤和溶解。反应10分钟后,将混合物用过量DCM/DMF(1∶1)洗涤。去除溶剂后,然后是添加10mL的DMF和搅拌3分钟,再次去除溶剂。添加10mL的去保护溶液(DMF中的20%哌啶)到反应器后,将混合物于室温搅拌10分钟,然后去除溶液。再次添加相同的量的去保护溶液和进行反应10分钟后,去除溶液,并且通过用DMF洗涤两次,用MC洗涤一次,及用DMF洗涤一次,各3分钟来制备Asp(tBu)-CTL树脂。添加10mL的DMF到另一反应器后,添加200mmol的Fmoc-Ala-OH(Bachem,Swiss),200mmol的HoBt和200mmol的Bop,并且通过搅拌良好溶解。经2遍添加400mmol的DIEA到反应器后,将混合物搅拌至少5分钟,直到全部固体溶解。将得到的氨基酸混合物溶液添加到含去保护的树脂的反应器,搅拌着于室温反应1小时。去除反应溶液后,然后是用DMF溶液搅拌3次,各5分钟,去除溶液。获取小量的反应的树脂,使经历Kaiser测试(茚三酮测试),以测定反应的程度。以如上所述的相同的方式通过用去保护溶液去保护2次来制备Ala-Asp(tBu)-CTL树脂。用DMF和MC充分洗涤后,再次进行Kaiser测试一次,以如上所述的相同的方式如下进行氨基酸附接。根据选定的氨基酸序列,以Fmoc-Pro,Fmoc-Arg(pbf),接头(Gly,Gly-Gly,Gly-Gly-Gly,Gly(4),氨基丁酸,氨基苯甲酸),Fmoc-His(trt),Fmoc-Glu(OtBu),Fmoc-Ile,Fmoc-Leu 和Fmoc-Glu(tBu)的顺序进行链反应。使Fmoc-保护基与去保护溶液反应两次各10分钟后,通过良好洗涤去除溶液。通过添加乙酸酐,DIEA和HoBt进行乙酰化1小时后,将制备的肽基树脂,各用DMF,MC和甲醇洗涤3次,通过缓慢通过氮气干燥,在减压下在P2O5存在下完全干燥,间歇搅拌下与30mL的离去溶液(含三氟乙酸95%,蒸馏水2.5%及茴香硫醚2.5%)于室温反应2小时。将树脂过滤和用小体积的TFA溶液洗涤,其后将滤出液与母液合并。在减压下蒸馏以将总体积减小至约一半后,通过添加50mL的冷醚诱导沉淀,和通过离心收集形成的沉淀,然后是用冷醚洗涤两次。去除母液后,将得到物在氮气氛下充分干燥,以获得1.11g的未纯化的Glu-Leu-Ile-Glu-His-接头-Arg-Pro-Ala-Asp肽(接头=Gly-Gly-Gly)(产率:88.2%)。使用分子量分析仪将分子量测量为1250.9(理论值:1250.35)。
【表1】
【测试例1:合成肽对细胞生长的效应】
为分析合成例中合成的肽的生长因子-样效应,使用HaCaT角质形成细胞(Korean细胞系库)和NIH3T3成纤维细胞(Korean细胞系库)根据Rizzino等人的方法(Rizzino et al.Cancer Res.48:4266(1988))进行磺基罗丹明B(SRB)测热测定。
在含10%胎牛血清(FBS;Sigma)的Eagle最小必需培养基(EMEM;Gibco,U.S.A.)的250mL组织培养瓶中分别培养HaCaT角质形成细胞和NIH3T3成纤维细胞。将培养的细胞用0.25%胰蛋白酶溶液处理,以将细胞从培养瓶底部分开,并离心来收集细胞沉淀。将它们悬浮于无FBS的EMEM,并且以4×103细胞/孔添加到96孔组织培养板的各孔。将细胞于37℃在7%CO2下培养24小时。24小时后,将培养基替换为新鲜的,含FBS的培养基,并将细胞在如上所述的相同的条件下与空白样品温育72小时而作为参照或与(100ng/mL)溶解于水和10%DMSO的灭菌的合成肽温育72小时。去除上清后,将细胞用磷酸缓冲盐水(PBS)洗涤一次。去除洗涤溶液和用SRB溶液处理后,然后是用PBS充分洗涤,在显微镜下观察细胞,以评估细胞活力。此外,在590nm处测量吸光度,以分析细胞增殖。
图2a和2b显示用肽处理后角质形成细胞(图2a)和成纤维细胞(图2b)的生长状态,及图3显示用肽处理后72小时的存活的角质形成细胞和成纤维细胞的显微镜图像。
如中图2a和2b所示,根据本发明的SEQ ID NO:1的肽促进角质形成细胞和成纤维细胞的生长。从图3看出,本发明的SEQ ID NO:1的肽促进角质形成细胞和成纤维细胞的生长。
【测试例2:促进合成肽的效应的层粘连蛋白和透明质酸产生】
将培养48小时的HaCaT细胞用在合成例中合成的肽处理。72小时后,将层粘连蛋白和透明质酸的水平测量为显示改善皮肤皱纹的指标。使用层粘连蛋白ELISA试剂盒(Takara,Japan)和透明质酸ELISA试剂盒(Takara,Japan)进行测量。显示,本发明的SEQ ID NO:1的肽增加成纤维细胞中层粘连蛋白(图4a)和透明质酸(图4b)的产生。
总结测试例1和2的结果,其可观察到,本发明的SEQ ID NO:1的肽呈现优秀的皮肤改善效应。
【测试例3:通过合成肽的黑色素色素的还原】
为了研究合成例中合成的肽针对生长因子BMP-4的拮抗剂活性,培养C57BL/6小鼠黑色素细胞(Jung Ang Lab.Animal,韩国),并且用α-黑色素细胞刺激激素(α-MSH;Sigma)诱导黑色素产生。然后,用BMP-4(R&D Systems,Inc.,美国)处理后,然后立即用不同的浓度的合成肽处理后,检查了是否被BMP抑制的黑色素产生再次活化。使用含10%FBS(Sigma)的DMEM(Sigma)于37℃在5%CO2下培养小鼠黑色素细胞。在24-孔板以1×105细胞/孔培养细胞并且确认细胞的附着后,将细胞仅用溶剂(对照),用200μg/mL α-MSH(阳性对照)或用1μg/mL BMP-4处理。然后,将细胞用SEQ ID NO:1的肽处理。将测试物质添加到各皿后,将细胞培养3天。通过将成分溶解到溶剂中,并且使用丙二醇∶乙醇∶纯水的5∶3∶2混合物溶剂稀释到测试浓度来制备测试物质。通过离心去除培养基后,可裸眼观察黑色素的产生。如中图5所示,α-MSH-处理的组显示黑色素产生的显著增加。肽-处理的组显示黑色素产生相当于α-MSH-处理的组。这表明用肽适当处理抑制BMP-4活性,并由此增加黑色素产生。
为了更精确的测量,将细胞用PBS洗涤和用1N氢氧化钠裂解。然后,在400nm处测量吸光度后,根据Dooley的方法计算黑色素产生的抑制(Dooley,T.P.et al.,Skin Pharmacol.7:188-200(1994)),及结果显示于图6。显示于图6的结果与图5的一致。
【测试例4:合成肽与BMP4的结合】
为了研究是否根据本发明合成的肽结合BMP蛋白,使用允许检测药物和受体之间的结合的Biacore仪器。
将6000应答单位(RU)的rh-BMP4蛋白(R&D Systems,Inc.,美国)通过胺化固定到可商购的CM5传感器芯片(Biacore,Sweden)。然后,以5μL/min的速度通过HBS-EP缓冲液(Biacore,Sweden),以活化CM5传感器芯片上的BMP4蛋白。为反应最优化后,以不同的浓度(1000μg/mL,500μg/mL,250μg/mL,125μg/mL,62.5μg/mL,31.3μg/mL,15.6μg/mL,7.8μg/mL,4μg/mL)通过合成肽。可由RU值的增加鉴定BMP4和合成肽之间的结合。如中图7所示,BMP4蛋白和合成肽显示非常强结合能力。此提示,SEQ ID NO:1的肽具有针对BMP-4的拮抗剂活性。
【测试例5:合成肽和BMP蛋白之间的免疫结合】
将合成例中制备的肽的N-末端用生物素(Sigma,美国)修饰。为了链霉亲和素层析,将生物素化的肽装载到填充有链霉亲和素-附接的树脂的柱,及用20mM磷酸钠缓冲液平衡。然后,使rh-BMP4蛋白(R&D Systems,Inc.,美国)通过柱后,使200mM磷酸钠缓冲液通过来冲洗未结合的蛋白,并将结合到生物素化的肽的蛋白通过用0.2M NaCl洗脱来分级分离。将洗出液通过SDS-PAGE分析(见图8a),并通过使用抗-BMP4抗体(Santa Cruz,美国)的蛋白印迹确证是否BMP4蛋白与生物素化的肽结合(见图8b)。如中图8b所示,BMP4蛋白结合到生物素化的肽。此提示,BMP4蛋白非常强烈结合SEQ ID NO:1的肽。
【测试例6:合成肽的热稳定性】
将合成例中制备的肽和(头蛋白,FGF-10)购自NIBSC(UK)的参照生长因子制备成0.11mg/mL磷酸盐缓冲溶液。1mL的各制备的溶液放入玻璃瓶和保持于37℃。在第0,5,10,20,30,40和70天采集溶液。离心去除任何变性的肽或蛋白后,使上清经历HPLC用于定量(图9)。如中图9所示,本发明的肽相比既有的头蛋白肽呈现优秀得多的热稳定性。
【实施例2:纳米肽的制备】
精确称重50mg的合成例中制备的肽,并且通过充分摇动溶解到500mL的蒸馏水中。将得到的溶液与5g的卵磷脂,0.3mL的油酸钠,50mL的乙醇和小量的油混合,然后用蒸馏水将体积调至1L。将溶液在高压下使用显微荧光计制备成100nm尺寸的纳米体。制备的纳米体的终浓度为约50ppm,且将它们用作化妆品的成分。
【制剂例1:润肤液】
根据通常采用的方法如下制备含实施例2中制备的肽纳米体的润肤液。
【表2】
成分 | 含量(wt%) |
肽纳米体 | 0.001 |
1,3-丁二醇 | 6.0 |
甘油 | 4.0 |
PEG 1500 | 1.0 |
透明质酸钠 | 1.0 |
聚山梨酯20 | 0.5 |
乙醇 | 8.0 |
防腐剂和色素 | 足量 |
二苯甲酮-9 | 0.05 |
香料 | 痕量 |
纯水 | 余量 |
总 | 100 |
【制剂例2:营养霜】
根据通常采用的方法如下制备含实施例2中制备的肽纳米体的营养霜。
【表3】
成分 | 含量(wt%) |
肽纳米体 | 0.001 |
白池花油 | 3.0 |
鲸蜡硬脂醇 | 1.5 |
硬脂酸 | 1.5 |
甘油基硬脂酸酯 | 1.5 |
液状石蜡 | 10.0 |
蜂蜡酸酯 | 2.0 |
聚山梨酯60 | 0.6 |
倍半油酸山梨糖醇酐 | 2.5 |
角鲨烷 | 3.0 |
1,3-丁二醇 | 3.0 |
甘油 | 5.0 |
三乙醇胺 | 0.5 |
生育酚乙酸酯 | 0.5 |
防腐剂和色素 | 足量 |
香料 | 足量 |
纯水 | 余量 |
总 | 100 |
【制剂例3:营养洗液】
根据通常采用的方法如下制备含实施例2中制备的肽纳米体的营养洗液。
【表4】
成分 | 含量(wt%) |
肽纳米体 | 0.002 |
1,3-丁二醇 | 4.0 |
甘油 | 4.0 |
鲸蜡硬脂醇 | 0.8 |
甘油基硬脂酸酯 | 1.0 |
三乙醇胺 | 0.13 |
生育酚乙酸酯 | 0.3 |
液状石蜡 | 5.0 |
角鲨烷 | 3.0 |
澳洲坚果坚果油 | 2.0 |
聚山梨酯60 | 1.5 |
倍半油酸山梨糖醇酐 | 0.5 |
羧基乙烯基聚合物 | 1.0 |
防腐剂和色素 | 足量 |
香料 | 足量 |
纯水 | 余量 |
总 | 100 |
【制剂例4:精华液】
根据通常采用的方法如下制备含实施例2中制备的肽纳米体的精华液。
【表5】
成分 | 含量(wt%) |
肽纳米体 | 0.005 |
甘油 | 10.0 |
1,3-丁二醇 | 5.0 |
PEG 1500 | 2.0 |
尿囊素 | 0.1 |
d/l-泛醇 | 0.3 |
EDTA-2Na | 0.02 |
羟乙基纤维素 | 0.1 |
透明质酸钠 | 8.0 |
羧基乙烯基聚合物 | 0.2 |
三乙醇胺 | 0.18 |
辛基十二醇聚醚-16 | 0.4 |
乙醇 | 6.0 |
香料,防腐剂和色素 | 足量 |
纯水 | 余量 |
总 | 100 |
【制剂例5:发油】
根据通常采用的方法如下制备含实施例2中制备的肽纳米体的发油。
【表6】
成分 | 含量(wt%) |
肽纳米体 | 0.005 |
甘油 | 7 |
1,3-丁二醇 | 5.0 |
PEG 1500 | 2.0 |
尿囊素 | 0.2 |
d/l-泛醇 | 0.3 |
EDTA-2Na | 0.02 |
羟乙基纤维素 | 0.2 |
透明质酸钠 | 3.0 |
羧基乙烯基聚合物 | 0.5 |
三乙醇胺 | 0.18 |
辛基十二醇聚醚-16 | 0.4 |
乙醇 | 4.0 |
香料,防腐剂和色素 | 足量 |
纯水 | 余量 |
总 | 100 |
【实施例3:合成肽的毛发生长促进效应】
为了研究合成例中合成的肽的毛发生长促进效应,使用毛去除霜部分去除小鼠(C57BL/6,Jung Ang Lab.Animal,韩国)背部毛。将10μL的SEQ ID NO:1的肽(1μg/μL)施用或施加到小鼠背部上部,及在第0,2和4天将10μL的PBS施用或施加到小鼠背部的更下部分。对于各例,观察10天毛发生长状态。本发明的肽在促进小鼠的毛发生长中有效(图10)。
虽然通过特定实施方式描述了本发明,其在不脱离后述权利要求中定义的本发明的精神和范围的情况下可进行各种变化和修饰对于本领域技术人员而言是显而易见。
Claims (12)
1.呈现生长因子活性的肽,其由以下通式1表示:
【通式1】
Glu-Leu-Ile-Glu-His-接头-Arg-Pro-Ala-Asp。
2.权利要求1的肽,其中所述接头包括多个氨基酸残基。
3.权利要求2的肽,其中所述接头包括2~10个Gly残基。
4.权利要求1的肽,其中所述肽具有促进细胞生长的能力。
5.权利要求1的肽,其中所述肽促进层粘连蛋白或透明质酸的产生。
6.权利要求1的肽,其中所述肽通过与骨形态生成蛋白(BMP)-2,BMP-4或BMP-7结合而呈现针对BMP-2,BMP-4或BMP-7的拮抗剂活性。
7.权利要求6的肽,其中所述肽呈现对于涉及BMP-2,BMP-4或BMP-7的疾病,病症或病情的预防或治疗效果,且所述疾病,病症或病情是脱发,炎症或骨疾病。
8.用于促进毛发生长的组合物,其包括根据权利要求1~6中任一项的呈现生长因子活性的肽作为活性成分。
9.用于改善皮肤状态的组合物,其包括根据权利要求1~6中任一项的呈现生长因子活性的肽作为活性成分。
10.抗炎症组合物,其包括根据权利要求1~6中任一项的呈现生长因子活性的肽作为活性成分。
11.用于预防或治疗骨疾病的组合物,其包括根据权利要求1~6中任一项的呈现生长因子活性的肽作为活性成分。
12.权利要求9的组合物,其中所述皮肤状态改善是皱纹改善,皮肤弹性改善,防止皮肤老化,改善皮肤保湿,去除老年斑,或治愈创伤。
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CN109715217B (zh) * | 2016-08-19 | 2022-07-29 | 凯尔格恩有限公司 | 米诺地尔和肽的结合物 |
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JP2012515769A (ja) | 2012-07-12 |
WO2010085039A3 (ko) | 2010-09-16 |
EP2383283B1 (en) | 2015-07-08 |
KR101163171B1 (ko) | 2012-07-19 |
WO2010085039A2 (ko) | 2010-07-29 |
EP2383283A2 (en) | 2011-11-02 |
US20110312884A1 (en) | 2011-12-22 |
ES2548982T3 (es) | 2015-10-22 |
CN102348716B (zh) | 2014-07-16 |
US8729028B2 (en) | 2014-05-20 |
KR20100085407A (ko) | 2010-07-29 |
JP5492226B2 (ja) | 2014-05-14 |
EP2383283A4 (en) | 2012-07-04 |
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