CN113271957A - 防止皮肤老化及皱纹改善用肽及包含其的组合物 - Google Patents
防止皮肤老化及皱纹改善用肽及包含其的组合物 Download PDFInfo
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- CN113271957A CN113271957A CN202080008686.2A CN202080008686A CN113271957A CN 113271957 A CN113271957 A CN 113271957A CN 202080008686 A CN202080008686 A CN 202080008686A CN 113271957 A CN113271957 A CN 113271957A
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- skin aging
- preventing skin
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Abstract
本发明涉及防止皮肤老化及皱纹改善用肽及包含其的组合物,更详细地,涉及包含甘氨酸(glycine)‑组氨酸(histidine)‑赖氨酸(l ysine)三肽(tripeptide)以及与上述三肽的羧基末端相连接的聚精氨酸(polyarginine)的新的防止皮肤老化及皱纹改善用肽及包含上述肽的防止皮肤老化及皱纹改善用组合物。本发明实施例的肽及组合物相比于现有的GHK三肽,可快速且有效地流入细胞质内,相比于GH K三肽,在低浓度中也能够以类似的水平防止皮肤老化,改善皱纹。
Description
技术领域
本发明涉及防止皮肤老化及皱纹改善用肽及包含其的组合物,更详细地,涉及包含甘氨酸(glycine)-组氨酸(histidine)-赖氨酸(l ysine)三肽(tripeptide)及与上述三肽的羧基末端相连接的聚精氨酸(polyarginine)的防止皮肤老化及皱纹改善用肽及包含上述肽的防止皮肤老化及皱纹改善用组合物。
背景技术
肽为作为蛋白质结构要素的氨基酸通过肽键连接而成的物质,是指包含2~50个左右氨基酸残基。肽医药品通过从蛋白质中筛选具有所需的生理活性的最小单位而成,像这样,使特定分子或特定信号传输系统起到靶作用的肽医药品具有生物体亲和性、活性特异性,因而副作用少,能够以少量呈现强烈的药理作用,在开发新药方面,相比于低分子化合物,临床阶段成功率呈现高。并且,对于肽医药品而言,在制备方面,作为肽的结构要素的氨基酸种类为20种,且容易制备和变形,因而具有容易管理质量及产业化的优点,从而以治疗疾病和美容的目的开发多种肽新药。
作为肽医药品的例,有被称为三肽-1(tripeptide-1)的甘氨酸-组氨酸-赖氨酸(glycine-histidyl-lysine)三肽(以下,GHK)。GHK原本为少量存在于人的血浆、唾液及小便的肽,20岁时,以200ng/ml左右存在于血浆内,60岁时,减少到80ng/ml,伴随这种减少和老化而出现的体内的明显再生力减少时间点呈现一致。据报告,GHK具有治愈伤口,增进移植皮肤的定植,抗炎,促进血管形成等皮肤再生相关多种效果。
肽医药品因亲水性而难以渗透包围个别细胞的脂质膜,因而当上述医药品的靶存在于细胞内时,需要通过质膜的战略,其包括对于口腔、鼻腔、肺、脑等,横穿以融合膜(tight junction)连接而形成致密的屏障的皮膜(epithelium)或内皮(endothelium)。开发用于将肽药物传递到细胞内的多种战略,作为其例,可例举利用细胞穿透肽(Cellpenetrating peptide,CPP)、病毒纳米粒子(viral nanoparticl e或virus-likeparticle)、脂质体(liposome)或外泌体(exosome)、脱氧核糖核酸(DNA)纳米线团(DNAnanoclew)、碳纳米管(car bon nanotube)、二氧化硅纳米粒子(silica nanoparticle)、金纳米粒子(gold nanoparticle)等的方法。
GHK三肽同样也是亲水性肽,难以渗透细胞,因而为了克服这种情况,研究出几种分子变形。例如,Lintner and Peschard(Int J Cosmet Sci.2000Jun;22(3):207-18.)示出通过在GHK粘附作为亲油性基团的棕榈酰(palmitoyl)基团(以下pal-GHK),GHK能够以100至10000倍左右进入细胞中。但是,pal-GHK在与未粘附有棕榈酰基团的GHK相同的浓度范围内呈现类似水平的效果,这表明如上所述的变形未增强效果。并且,据报告,Lim等人.(J Cosmet Sci.2003Sep-Oct;54(5):483-91.)在GHK的氨基末端结合被众所周知为CPP的9个赖氨酸(K9-GHK),同样对于细胞,与GHK相比较时,在相同浓度中呈现类似水平的效果。
即,存在有通过分子变形提高GHK的渗透率的发明,但尚未公开与此同时可提高效果的分子变形,尤其尚未公开在三肽的羧基末端连接聚精氨酸的肽,因此未指出这种变形的肽的效果。
发明内容
技术问题
本发明是为了解决上述的要求而研究出的,本发明的一实施例提供包含甘氨酸(glycine)-组氨酸(histidine)-赖氨酸(lysine)三肽及与上述三肽的羧基末端相连接的聚精氨酸(polyarginine)的防止皮肤老化及皱纹改善用肽。
并且,本发明的一实施例提供包含上述肽的防止皮肤老化及皱纹改善用组合物。
本发明的一实施例提供包括将包含上述肽的组合物给药到对象的方法的防止皮肤老化及皱纹改善方法。
本发明要解决的技术问题不局限于以上所提及的技术问题,本发明所属技术领域的普通技术人员可从以下的记载内容中明确地理解未提及的其他技术问题。
解决问题的方案
为了实现上述技术问题,本发明一实施方式的防止皮肤老化及皱纹改善用肽包含:甘氨酸(glycine)-组氨酸(histidine)-赖氨酸(lysine)三肽(tripeptide);以及与上述三肽的羧基末端相连接的聚精氨酸(polyarginine)。
其中,在上述肽的胺末端可结合有亲油性酰基(acyl)官能团。
上述酰基官能团的碳原子数可以为1至15。
上述酰基官能团可由包含三个以上碳原子的亲油性基团形成共价键,上述酰基官能团可以为选自丙酰基、己酰基、月桂基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油基、二十烷酰基、二十二烷酰基、乙酰基、丙基、己基、十二烷基、肉豆蔻基、十六烷基、十八烷基、二十烷基及二十二烷基中的一种基团。
上述聚精氨酸可连接有2个至8个精氨酸。
本发明再一实施方式的防止皮肤老化及皱纹改善用组合物包含上述肽。
其中,本发明的特征在于,上述组合物可包含0.1至1000μM的上述肽。本发明的特征在于,在上述组合物中,上述肽不包含亲油性基团,上述组合物可包含10至1000μM的上述肽。本发明的特征在于,在上述组合物中,上述肽包含亲油性基团,包含0.1至10μM的上述肽。并且,以总组合物为基准,可包含10ppm(0.001%)至100000ppm(10%)的上述肽。
上述组合物还可包含药学或化妆品学上可接受的载体。
上述组合物可具有选自由溶液、外用软膏、乳霜、泡沫、营养化妆水、柔软化妆水、面膜、柔软水、乳液、隔离霜、精华素、香皂、液体清洁剂、入浴剂、防晒霜、防晒油、悬浮液、乳浊液、糊剂、啫喱、护肤液、粉饼、含表面活性剂的洁面乳、油、粉底、乳浊液粉底、蜡粉底、贴片(patch)及喷剂组成的组中的剂型。
本发明的防止皮肤老化及改善皱纹方法包括将根据另一实施方式的包含上述肽的组合物给药到对象的方法。
上述对象可以为人类或啮齿类(如大鼠、小鼠或豚鼠)等实验动物,可以为需要改善皮肤皱纹及防止老化的对象。
上述给药可以为经皮给药。在本发明中,经皮给药是指局部给药到皮肤,使药学组合物所含的有效量的活性成分传递到皮肤内。
上述的解决问题的方案仅用于例示,不应被解释为限制本发明的意图。除了上述的例示性实施例之外,附图及发明的详细说明中可存在追加的实施例。
发明的效果
本发明新公开在羧基末端连接有聚精氨酸(polyarginine,以下R4)的甘氨酸-组氨酸-赖氨酸三肽及亲油性基团形成共价键,在羧基末端连接有聚精氨酸(polyarginine)的甘氨酸-组氨酸-赖氨酸三肽,公开这些肽对皮肤的提高的效果及包含其的组合物。
本发明实施例的肽及包含上述肽的组合物可相比于GHK快速且有效地流入细胞质内。如此流入的上述肽及组合物尤其具有通过紫外线(UV)抑制增加表达的蛋白质分解酶的活性,使通过UV抑制的胶原蛋白合成恢复的效果。
并且,本发明的肽及组合物容易流入细胞质,因而即使相比于GHK,以低浓度使用,也可具有类似水平的防止皮肤老化及皱纹改善效果,因而具有经济、在高浓度中也几乎无细胞毒性而可长期使用的优点。
本发明的效果不局限于上述的效果,应当理解为包括可从本发明的详细说明或权利要求书中所记载的发明的结构中推论的所有效果。
附图说明
图1为GHK及本发明的肽对细胞产生的影响比较。
图2为GHK及本发明的肽的细胞内渗透程度比较。
图3为GHK及本发明的肽对紫外线诱导的基质金属蛋白酶-2(UV-induced MMP-2)活性产生的效果比较。
图4为GHK及本发明的肽对UV照射的细胞的胶原蛋白合成产生的效果比较。
图5为GHK及本发明的肽对UV照射的细胞的MMP-9活性产生的效果比较。
具体实施方式
以下,更详细说明本发明。但是本发明能够以多种不同的形态实现,本发明不局限于在此说明的实施例,本发明仅根据所附的权利要求书定义。
进而,本发明中使用的术语仅用于说明特定的实施例,并不是限定本发明的意图。除非上下文有明确不同的含义,则单数的表现包括复数的表现。在本发明的说明书全文中,除非有特别反对的记载,则“包括”一个结构要素是指还可包括另一结构要素,并不将另一结构要素排除在外。
追加地,存在于本发明中说明的任意肽的氨基酸可以为L-氨基酸或D-氨基酸。优选地,可以为L-氨基酸。
本发明一实施方式的防止皮肤老化及皱纹改善用肽包含甘氨酸(glycine)-组氨酸(histidine)-赖氨酸(lysine)三肽(tripeptide)及与上述三肽的羧基末端相连接的聚精氨酸(polyarginine)。
据报告,如上所述,甘氨酸(glycine)-组氨酸(histidine)-赖氨酸(lysine)三肽(tripeptide)(以下GHK)具有多种皮肤再生相关效果。尤其,GHK被熟知在成纤维细胞中使构成胶原蛋白(collagen)、弹性蛋白(elastin)、糖胺聚糖(glycosaminoglycan)等细胞外基质(extracellular matrix)的物质的合成增加。这种细胞外基质为皮肤的主要构成物质,可起到保护层及新的成纤维细胞可生长的基质的作用,当皮肤的细胞外基质减少时,出现皱纹变多且变深,皮肤下垂等老化的状态。
其中,上述聚精氨酸(Rx,x=精氨酸的数量)可连接有2个至8个精氨酸,优选地,可连接有4至8个,最优选地,可连接有4个。据报告,聚精氨酸被熟知为细胞穿透肽,更详细地,包含6个至15个精氨酸的聚精氨酸与精氨酸的数量成正比地具有细胞渗透效果,当精氨酸为5个以下时,几乎无法渗透。本发明的发明人指出将聚精氨酸与上述三肽的羧基末端相连接时,包含4个精氨酸的聚精氨酸也可提高细胞渗透。
上述防止皮肤老化及皱纹改善用肽,除了包含作为L-氨基酸或D-氨基酸的GHK三肽及与上述三肽的羧基末端相连接的聚精氨酸的肽之外,还包含其反向翻转(retroinverso)类似物。反向翻转类似物是指相比于特定肽,氨基酸序列倒置,氨基酸的α中心的分子不对称性(chirality)也逆转的(inverted)类似物。尤其,由L-氨基酸构成的肽的反向翻转类似物不易分解,药效可更持久,设计好时,对于原始肽的靶,起到与原始肽类似的相互作用,可呈现相同的药效。
上述肽可在胺末端由亲油性酰基(acyl)官能团(RCO-)形成共价键,上述酰基官能团的R可以为碳原子数为1至15的直链或支链烷基或烯基基团。例如,本发明的特征在于,上述肽可由包含三个以上碳原子的亲油性基团形成共价键。本发明的特征在于,上述亲油性基团可以为选自丙酰基(propionyl)、己酰基(caproyl)、月桂基(lauryl)、肉豆蔻酰基(myristoyl)、棕榈酰基(palmitoyl)、硬脂酰基(stearoyl)、油基(oleyl)、二十烷酰基(eicosanoyl)、二十二烷酰基(docosanoyl)、乙酰基(acetyl)、丙基(propyl)、己基(hexyl)、十二烷基(dodecyl)、肉豆蔻基(myristyl)、十六烷基(hexadecyl)、十八烷基(octadecyl)、二十烷基(eicosanyl)及二十二烷基(docosanyl)中的一种基团,优选地,可以为棕榈酰基团。上述亲油性基团可来源于饱和的不饱和或饱和脂肪酸。上述亲油性基团可与氨基末端的胺基团或赖氨酸的支链胺基团相连接,优选地,可与氨基末端的胺基团相连接。
上述肽可具有防止皮肤的老化,改善皱纹的效果。据报告,皮肤老化的最大原因为紫外线,紫外线被熟知尤其分解胶原蛋白等细胞外基质,增加主要分解上述细胞外基质的基质金属蛋白酶(matrix metalloproteinase,以下MMP)的表达。本发明一实施方式的肽可减少因UV而增加的MMP的表达及活性,可增加因UV而减少的胶原蛋白合成。这种胶原蛋白的增加可改善皱纹,防止皮肤的老化。尤其,相比于被熟知具有防止皮肤老化及皱纹改善效果的GHK,本发明一实施方式的不包含或包含亲油性基团的GHK-Rx在细胞内的渗透力可得到提高,可在相对低的浓度中,以类似的水平呈现上述的防止皮肤老化及皱纹改善效果。
本发明一实施方式的肽可通过该领域中公知的肽合成方法制备而成。上述肽合成方法大致有化学合成方法和生物学合成方法,本发明一实施方式的肽优选地通过化学合成方法,最优选地通过固相合成方法(solid phase synthesis method)制备而成。生物学合成方法包括利用遗传工学技术,例如将对所需的肽编码的碱基序列导入于蛋白质表达载体,在细菌中诱导表达之后分离的方法等。
本发明再一实施方式的防止皮肤老化及皱纹改善用组合物包含上述肽。
其中,本发明的特征在于,上述组合物可包含0.1至1000μM的上述肽。本发明的特征在于,在上述组合物中,上述肽不包含亲油性基团,上述组合物可包含10至1000μM的上述肽。本发明的特征在于,在上述组合物中,上述肽包含亲油性基团,上述组合物可包含0.1至10μM的上述肽。对于包含亲油性基团的组合物而言,即使在相对低的浓度中也可呈现相同的效果。这是因为当上述组合物包含过少量的上述肽时,有可能无法充分得到利用上述肽的防止皮肤老化及皱纹改善效果,当包含过量时,有可能具有细胞毒性。
当上述组合物为化妆品组合物时,在总化妆品组合物中,可包含10ppm(0.001重量百分比)至100000ppm(10重量百分比)的上述肽。
追加地,上述肽可以为未结合有铜的形态。上述肽可以为结合有(bound)铜的形态,此时,铜与上述肽之比可以为1:2。GHK可利用氨基末端,即甘氨酸的胺基团及组氨酸的支链具备对铜的亲和力(affinity)与其形成复合物发挥功能,但无铜也可具有生理活性。尤其,在GHK的氨基末端结合有亲油性基团时,对如上所述的胺基团的铜结合的贡献度降低,即使亲和力下降,也可呈现与未结合有亲油性基团的GHK类似水平的效果。
在上述本发明一实施方式的组合物中,除了上述肽之外,还可多样地添加药学或化妆品学上可接受的盐、载体、赋形剂、媒介及可更加增进皮肤的老化防止及皱纹改善效果的其他添加剂等。
上述组合物还可包含制备药学组合物时通常使用的适当的载体、赋形剂及稀释剂。本发明的组合物可分别通过通常的方法以散剂、颗粒剂、片剂、胶囊剂、悬浮液、乳液、糖浆、气溶胶等口服型剂型、外用剂、栓剂及灭菌注射溶液的形态剂型化来使用,作为可包含在组合物中的载体、赋形剂及稀释剂,可例举乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油。当制剂化时,使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋形剂调配。对于本发明的组合物而言,作为有效成分的多功能性皮肤渗透肽优选为经皮给药制剂形态。
上述组合物还可包含一种以上的调配于一般皮肤化妆品的化妆品学上可接受的载体,作为常规的成分,例如,可适当调配油分、水、表面活性剂、保湿剂、低级醇、增粘剂、螯合剂、色素、防腐剂、香料等,但不局限于此。
上述组合物可具有选自由溶液、外用软膏、乳霜、泡沫、营养化妆水、柔软化妆水、面膜、柔软水、乳液、隔离霜、精华素、香皂、液体清洁剂、入浴剂、防晒霜、防晒油、悬浮液、乳浊液、糊剂、啫喱、护肤液、粉饼、含表面活性剂的洁面乳、油、粉底、乳浊液粉底、蜡粉底、贴片(patch)及喷剂组成的组中的剂型。
以下,详细说明本发明的实施例,可使本发明所属技术领域的普通技术人员容易实施。但是本发明能够以多种不同的形态实现,不局限于在此说明的实施例。
本发明的新肽通过固相肽合成法合成,利用HPLC和LC-MS分析合成的肽。
实施例1.H-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL-树脂(resin)的合成
a.H-Arg(Pbf)-CTL树脂的合成:将2-氯三苯甲基氯(2-Chloro trityl chloride)树脂(珠科技(BeadTech)公司,1%二乙烯基苯(DVB)交联(crosslinked),100~200目(mesh),1.41mmol/g)7g(10mmol)放入反应容器中,添加二氯甲烷(MC)40mL,搅拌30分钟。去除溶液,放入二甲基甲酰胺(DMF)40mL,搅拌30分钟之后,重新去除溶剂。在反应容器中,放入Fmoc-Arg(Pbf)-OH 6.4g(1eq)和DMF 40mL、二异丙基乙胺(DIPEA)5.3mL(3eq)反应1小时之后,过滤,利用DMF 40mL洗涤之后,放入MC:MeOH:DIPEA(17:2:1)的溶液40mL进行反应(capping)。反应1小时之后,过滤反应溶液,然后利用20%哌啶/DMF溶液40mL以每次30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次。
b.H-Arg(Pbf)Arg(Pbf)-CTL树脂的合成:在a中合成的H-Arg(Pbf)-CTL树脂中分别将Fmoc-Arg(Pbf)-OH 8.4g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU 5.7g(1.5eq)溶解于DMF20mL来添加,追加DIPEA5.2mL(3eq)进行反应。反应3小时之后,通过茚三酮检测(Kaisertest)确认反应结束,之后,过滤反应溶液来去除之后,利用20%哌啶/DMF溶液40mL以每30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次,合成H-Arg(Pbf)Arg(Pbf)-CTL树脂。
c.通过连续反应的H-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂合成:以与b相同的方法使b中合成的H-Arg(Pbf)Arg(Pbf)-CTL树脂与Fmoc-Arg(Pbf)-OH反应之后,通过茚三酮检测及脱保护基反应导入H-Arg(Pbf),然后,连续反应2次,合成H-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
实施例2.Boc-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL
树脂合成
a.在上述实施例1中合成的H-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加少量的MC之后,分别将Fmoc-Lys(Boc)-OH 6.1g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU5.7g(1.5eq)溶解于DMF 20mL来添加,追加DIPEA5.2mL(3eq)进行反应。反应4小时之后,通过茚三酮检测确认反应结束,然后,过滤反应溶液来去除之后,利用20%哌啶/DMF溶液40mL以每30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次,合成H-Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
b.在H-Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加少量的MC浸湿树脂之后,分别将Fmoc-His(Trt)-OH 8.1g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU 5.7g(1.5eq)溶解于DMF 20mL来添加,追加DIPEA 5.2mL(3eq)进行反应。反应4小时之后,通过茚三酮检测确认反应结束,然后,过滤反应溶液来去除之后,利用20%哌啶/DMF溶液40mL以每30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次,合成H-His(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
c.在H-His(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加MC浸湿树脂之后,分别将Boc-Gly-OH2.3g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU 5.7g(1.5eq)溶解于DMF 20mL来添加,追加DIPEA 5.2mL(3eq)进行反应。反应4小时之后,通过茚三酮检测确认反应结束,然后,过滤反应溶液来去除之后,过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤3次,合成Boc-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
实施例3.Pal-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL
树脂的合成
a.在上述实施例1中合成的H-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加少量的MC之后,分别将Fmoc-Lys(Boc)-OH 6.1g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU5.7g(1.5eq)溶解于DMF 20mL来添加,追加DIPEA5.2mL(3eq)进行反应。反应4小时之后,通过茚三酮检测确认反应结束,然后,过滤反应溶液来去除之后,利用20%哌啶/DMF溶液40mL以每30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次,合成H-Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
b.在H-Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加少量的MC浸湿树脂之后,分别将Fmoc-His(Trt)-OH 8.1g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU 5.7g(1.5eq)溶解于DMF 20mL来添加,追加DIPEA 5.2mL(3eq)进行反应。反应4小时之后,通过茚三酮检测确认反应结束,然后,过滤反应溶液来去除,利用20%哌啶/DMF溶液40mL以每30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次,合成H-His(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
c.在H-His(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加MC浸湿树脂之后,分别将Fmoc-Gly-OH 3.9g(1.3eq)和HOBt 2.0g(1.3eq)及HBTU 5.7g(1.5eq)溶解于DMF 20mL来添加,追加DIPEA 5.2mL(3eq)进行反应。反应3小时之后,通过茚三酮检测确认反应结束,然后,过滤反应溶液来去除之后,利用20%哌啶/DMF溶液40mL以每30分钟脱保护反应2次。过滤反应液,利用DMF 40mL洗涤3次,利用MC 40mL洗涤1次,合成H-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂。
d.添加浸湿H-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂程度的MC之后,追加DMF 40mL,然后添加棕榈酰氯(palmitoyl chloride)3.5g(1.3eq)和DIPEA 5.2mL(3eq)进行反应,4小时之后,通过茚三酮检测确认反应。反应结束之后,过滤反应液,然后,利用DMF 40mL洗涤3次,利用MC 40mL洗涤3次。
实施例4.H-ArgArgArgArg-OH(R4)的合成
在实施例1中合成的H-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL-树脂中添加5%反式脂肪酸(TFA)/MC(mL),从树脂中脱漏反应30分钟。收集反应3次的滤液浓缩反应物之后,添加95%TFA和5%H2O溶液50mL搅拌3小时去除保护基,然后浓缩,将滤液分散于醚(ether)中,回收粗(crude)R4。在粗R4肽中添加蒸馏水溶解之后,利用制备液相色谱仪(prep-LC)(column ID 5cm)纯化之后,冷冻干燥,得到白色的粉末1.7g(纯度99.1%(高效液相色谱仪,HPLC),收率(26.6%)),利用液相色谱-质谱联用仪(LC-MS)的分子量测定为643.40(M+1),(理论值:M=642.42)。
实施例5.H-GlyHisLys-ArgArgArgArg-OH(GHK-R4)的合成
在实施例2中合成的Boc-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加5%TFA/MC(mL),从树脂中脱漏反应30分钟。收集反应3次的滤液浓缩反应物之后,添加95%TFA和5%H2O溶液60mL搅拌4小时去除保护基,然后浓缩,将滤液分散于醚中,回收粗GHK-R4。在粗GHK-R4肽中添加蒸馏水溶解之后,利用制备液相色谱仪(column ID 5cm)纯化之后,冷冻干燥,得到白色的粉末3.6g(纯度99.2%(HPLC),收率(37.3%)),利用LC-MS的分子量测定为965.60(M+1),(理论值:M=964.59)。
实施例6.Pal-GlyHisLys-ArgArgArgArg-OH(Pal-GHK-R4)的合成
在实施例3中合成的Pal-GlyHis(Trt)Lys(Boc)-Arg(Pbf)Arg(Pbf)Arg(Pbf)Arg(Pbf)-CTL树脂中添加5%TFA/MC(mL),从树脂中脱漏反应30分钟。收集反应3次的滤液浓缩反应物之后,添加95%TFA和5%H2O溶液60mL搅拌4小时去除保护基,然后浓缩,将滤液分散于醚中,回收粗Pal-GHK-R4。在粗Pal-GHK-R4肽中添加蒸馏水溶解之后,利用制备液相色谱仪(柱ID 5cm)纯化之后,冷冻干燥,得到白色的粉末3.4g(纯度99.5%(HPLC),收率(28.2%)),利用LC-MS的分子量测定为1203.80(M+1),(理论值:M=1202.82)。
实验例1.新肽的毒性检查
为了了解本发明实施例的新肽(GHK-R4及Pal-GHK-R4)对细胞产生的毒性,进行MTT assay。此时,作为对照组,使用GHK-醋酸酯(acetate),分别按不同浓度将对照组和新肽处理于成纤维细胞,24小时之后,处理MTT试剂,然后,测定吸光度,从中求出细胞的生存率。
其结果如图1所示,三种肽全部呈现在高浓度中也几乎不出现细胞毒性。GHK-醋酸酯的IC30值大致计算为31.71mM,GHK-R4计算为5.32mM,Pal-GHK-R4计算为8.70μM。
实验例2.新肽的细胞内渗透分析
对Hs68成纤维细胞将50μM GHK-醋酸酯和GHK-R4处理1小时、3小时之后,通过共聚焦显微镜拍摄细胞内渗透程度,其结果如图2所示。将GHK-醋酸酯处理1小时时,GHK-醋酸酯几乎不进入细胞质内,当处理3小时时,一部分GHK-醋酸酯进入细胞质内。相反,可确认GHK-R4从1小时开始均进入细胞质内,GHK-R4相比于GHK-醋酸酯,更快速进入细胞内。即,当在GHK的羧基末端粘附有R4时,呈现细胞渗透速度及效率变高。
实验例3.对于UV-诱导的MMP-2活性的新肽的效果分析
为了评价在照射户外紫外线(UVB)的Hs68成纤维细胞中新肽对UV-诱导的MMP-2活性产生的效果,实施明胶酶谱法(gelatin zy mography)。MMP-2为当对成纤维细胞施加紫外线或氧化应激时增加的蛋白质分解酶。对Hs68成纤维细胞用UVB诱导氧化应激,按不同浓度处理各个肽之后,在上清液中测定MMP-2的活性度。GHK-醋酸酯、GHK-R4、Pal-GHK-R4全部抑制利用UVB诱导的MMP-2的活性,GHK-R4在相比于GHK-醋酸酯约1/10的浓度中且Pal-GHK-R4在GHK-醋酸酯的1/100浓度中呈现MMP-2抑制效果(图3)。即,当在GHK的羧基末端粘附有R4时,可在更低的浓度中抑制UV-诱导的MMP-2活性,当在此粘附棕榈酰基团时,呈现在更低于其的浓度中可抑制。
实验例4.对于胶原蛋白合成量的新肽的效果分析
测定在照射UVB的Hs68成纤维细胞中新肽对胶原蛋白合成量产生的影响。照射UVB之后,按不同浓度处理各个肽,使用上清液测定分泌的易溶(soluble)的胶原蛋白量。其结果,GHK-醋酸酯、GHK-R4、Pal-GHK-R4全部相比于UVB组,浓度依赖性地增加易溶胶原蛋白合成。此时,GHK-R4在GHK-醋酸酯的1/5浓度范围且Pal-GHK-R4在GHK-醋酸酯的1/100浓度范围内增加胶原蛋白合成(图4),这表明当在GHK的羧基末端粘附有R4和棕榈酰基团时,对于因UV而减少的胶原蛋白合成量,可在更低于GHK的浓度中增加。
实验例5.对于UV-诱导的MMP-9表达的新肽的效果分析
通过蛋白质印迹法(western blot)确认在照射UVB的Hs68成纤维细胞中新肽对MMP-9蛋白质表达变化产生的效果。MMP-9为利用明胶酶(gelatinase)如同MMP-2借助紫外线或氧化应激增加的蛋白质分解酶。照射UVB之后,当处理GHK-醋酸酯和新肽时,大致上,浓度依赖性地降低MMP-9的表达(图5),尤其,相比于GHK,GHK-R4和Pal-GHK-R4能够以更低的浓度抑制MMP-9表达。
综上所述,通过在羧基末端连接聚精氨酸,可将GHK三肽有效地导入到细胞内,相比于GHK三肽,可在低浓度中降低利用UV诱导的MMP-2/9的增加及胶原蛋白合成减少效果。此时,当在GHK-聚精氨酸中使亲油性基团形成共价键时,相比于GHK-聚精氨酸,更增加细胞内流入增加,可在更低的浓度中抑制因UV而呈现的负面效果。
上述的本发明的说明用于例示,本发明所属技术领域的普通技术人员应当理解,在不变更本发明的技术思想或必要特征的情况下,能够以其他具体的形态容易变形。因此,应理解为以上记述的多个实施例在所有方面是例示性的,而非限定。例如,以单一型说明的各个结构要素能够以分散的方式实施,同样,说明分散的多个结构要素也能够以结合的形态实施。
本发明的范围由所附的权利要求书表示,应解释为权利要求书的含义及范围以及从其等同概念导出的所有变更或变形的形态包括在本发明的范围内。
Claims (9)
1.一种防止皮肤老化及皱纹改善用肽,其特征在于,包含:
甘氨酸-组氨酸-赖氨酸三肽;以及
聚精氨酸,与所述三肽的羧基末端相连接。
2.根据权利要求1所述的防止皮肤老化及皱纹改善用肽,其特征在于,在所述肽的胺末端结合有亲油性酰基官能团RCO-,所述酰基官能团的碳原子数为1至15。
3.根据权利要求1或2所述的防止皮肤老化及皱纹改善用肽,其特征在于,所述聚精氨酸连接有2个至8个精氨酸。
4.一种防止皮肤老化及皱纹改善用组合物,其特征在于,包含权利要求1至3中任一项所述的肽。
5.根据权利要求4所述的防止皮肤老化及皱纹改善用组合物,其特征在于,所述组合物包含10ppm至100000ppm的所述肽。
6.根据权利要求4或5所述的防止皮肤老化及皱纹改善用组合物,其特征在于,所述肽不包含亲油性基团,所述组合物包含10至1000μM的所述肽。
7.根据权利要求4或5所述的防止皮肤老化及皱纹改善用组合物,其特征在于,所述肽包含亲油性基团,所述组合物包含0.1至10μM的所述肽。
8.根据权利要求4至7中任一项所述的防止皮肤老化及皱纹改善用组合物,其特征在于,所述组合物还包含药学或化妆品学上可接受的载体。
9.根据权利要求4至8中任一项所述的防止皮肤老化及皱纹改善用组合物,其特征在于,所述组合物具有选自由溶液、外用软膏、乳霜、泡沫、营养化妆水、柔软化妆水、面膜、柔软水、乳液、隔离霜、精华素、香皂、液体清洁剂、入浴剂、防晒霜、防晒油、悬浮液、乳浊液、糊剂、啫喱、护肤液、粉饼、含表面活性剂的洁面乳、油、粉底、乳浊液粉底、蜡粉底、贴片及喷剂组成的组中的剂型。
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