CN105324122B - 可用于治疗多种皮肤病的衍生自人类c-x-c趋化因子的四肽 - Google Patents
可用于治疗多种皮肤病的衍生自人类c-x-c趋化因子的四肽 Download PDFInfo
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- CN105324122B CN105324122B CN201480033362.9A CN201480033362A CN105324122B CN 105324122 B CN105324122 B CN 105324122B CN 201480033362 A CN201480033362 A CN 201480033362A CN 105324122 B CN105324122 B CN 105324122B
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Abstract
由(I或V)‑X1‑K‑X2组成的四肽呈现不同生物活性,其中X1可选自E、Q或K,且X2可选自M、F、I、W或V。所述肽为多功能效应分子,其刺激角质细胞迁移;中和诸如革兰氏阳性金黄色葡萄球菌的脂磷壁酸等细菌细胞壁组分的促炎性效应;并诱导所培养人类脐静脉内皮细胞中的血管生成。使用代表性肽的SOR‑300‑FT牛皮癣皮肤模型也展示促炎性病状的下调。在使用EPIDERMTM皮肤替代物处理正常皮肤组织时的基因谱分析研究也支持所述生物活性。具有不同生物活性的本发明肽可用于治疗多种皮肤病,包括但不限于急性或慢性伤口、膨胀纹、老化皮肤、毛发控制、诸如牛皮癣、异位性皮肤炎和酒糟鼻等炎症性皮肤,并用于去除不期望毛发或用于诸如去除皮赘等情况。
Description
本申请主张对于2013年6月14日提交的美国临时申请号61/835,424的优先权的益处,其以引用方式全文并入本文中。
技术领域
本发明涉及具有生物、美容和治疗活性的四肽。特定而言,本发明涉及衍生自若干C-X-C趋化因子的保守区的四肽。这些肽已显示促进细胞迁移、血管生成、中和细菌细胞组分(诸如LTA诱导的促炎性信号)、并刺激正常表皮皮肤替代物的活性。本发明还涉及使用这些肽促进伤口修复并治疗各种影响皮肤和其他相关体表(诸如口腔)的伤害的方法。
发明背景
角质细胞和真皮内皮细胞为调控皮肤伤口和溃疡的愈合的可溶性因子的主要来源。由于降低的活性而导致的异常(包括生长因子产生、血管生成反应、巨噬细胞功能、胶原累积、表皮障壁功能和角质细胞以及纤维母细胞迁移和增殖)均有助于缺陷性伤口愈合。生长因子和细胞因子已用于供治疗伤口的临床环境。实例包括(但不限于)已显示对罹患不同病因的多种伤口和慢性皮肤溃疡的患者的伤口愈合发挥有益效应的PDGF(血小板源生长因子(Rees等人,1999)和GM-CSF(粒细胞-巨噬细胞群落刺激因子),这些病因包括羟基脲相关的腿溃疡(Stagno等人,1999)、静脉腿溃疡(Da Costa等人,1999)、血红素病相关的溃疡(Voskaridou等人,1999)和由切除术导致的伤口(Gaches等人,1998)。向患有皮肤病灶的麻风患者真皮内施用GM-CSF也导致伤口愈合增强和角质细胞的数量和层增加(Kaplan等人,1992;Braunstein等人,1994)。
生长因子和细胞因子二者均为蛋白质。使用蛋白质治疗剂治疗表皮伤口的困难通常与所涉及蛋白质的大尺寸相关。天然蛋白质的复杂结构和制造成本对于广泛临床用途而言令人望而却步。制剂中的此类天然蛋白质的稳定性和兼容性也是主要问题。由于天然蛋白质的大尺寸而到达皮肤的目标层的渗透性较差常减少效力并解释蛋白质治疗剂的失败有益效应。为克服这些问题,携带大蛋白质的活性的短肽应满足较不昂贵、成本有效的产生以及处置和操纵简单的需求。另外,短生物活性肽因对蛋白酶较不敏感而被伤口组织较好地吸收并保留。短生物活性肽的吸收特征的优势也使其成为除护理急性和慢性伤口以外的用途、诸如治疗与老化和日晒相关的皮肤问题的可行选择。
趋化因子在结构上相关并代表具有不同生物活性的8kd至150kd蛋白质的较大超家族。它们通常在细胞刺激时分泌来在体内平衡期间以及在炎症期间控制白细胞运输,且对于先天性与适应性免疫间的联系是必要的。连同诸如整合素和选择蛋白等黏着分子,趋化因子及其受体主要用作促进具体细胞类型选择性移动至靶向组织微环境中并移动出所述微环境的复杂分子网络的一部分(Key等人,2003;Ono等人,2003)。趋化因子选择性介导嗜中性粒细胞、巨噬细胞和淋巴细胞的区域特异性募集。除了为趋化性因子以外,趋化因子也在体内平衡的维持、血管生成/血管抑制、细胞分化和活化、伤口愈合、肿瘤生长和转移、淋巴组织的淋巴细胞归巢和发育以及影响免疫反应的总体1型/2型平衡方面起重要作用(Behm等人,2012;Gillitzer等人,2001;Raman等人,2011;Romagnani等人,2004;Rossi等人,2000)。
由四半胱氨酸基序来定义,根据其胺基末端处的半胱氨酸残基的构型将趋化因子细分为四个不同家族。有两个较大亚家族CCL亚家族(CCL1至CCL28)和CXCL亚家族(CXCL1至CXCL16)以及两个较小亚家族XCL亚家族(XCL1至XCL2)和CX3CL1亚家族(Bacon等人,2003)。趋化因子的CXC亚家族在不同过程(包括炎症、伤口愈合、生长调控、血管生成和肿瘤生成)中起重要作用(Keeley等人,2008;2011)。许多趋化因子与内皮细胞和细胞外基质上的蛋白聚糖的糖胺聚糖(GAG)部分相互作用(Handel等人,2005)。充当硫酸肝素的模型化合物的肝素是在体内实际上每一个细胞上表达的最普遍的GAG类别。所有趋化因子均与肝素GAG相互作用。
在我们的研究中,注意到C-X-C趋化因子在其一级氨基酸序列中显示一些序列类似性但在二级结构中高度保守。九种人类C-X-C趋化因子的一级氨基酸序列的检查使用下文“本发明的详细说明,第1段落”中显示的每一个趋化因子的NCBI登录号揭露定位于处C末端部分处的参与GAG结合的高度保守区。我们自GAG结合区生成四肽并测试生物活性。令人惊奇地,所述四肽显示不同生物活性,包括促进角质细胞迁移、诱导人类脐静脉内皮细胞上的血管生成、中和LTA诱导的促炎性细胞因子和调节细胞生长和生长因子产生。所述四肽可用作用于改善多种皮肤病的药品和化妆品二者。
发明概述
本发明涉及可用于促进哺乳动物的伤口愈合的短生物活性肽。由分离肽优选地靶向的伤口为影响皮肤和相关黏膜表面的那些伤口。尽管并不限于任何特定机制,但本发明肽能够通过刺激细胞迁移和血管生成来影响伤口愈合。本发明肽可以体外和体内方式二者使用,并且能够诱导角质细胞的前述活性。
本发明的一个实施方案涉及式(I或V)-X1-K-X2的分离四肽,其中X1可选自E、Q和K;且X2可选自M、F、I、W、V和L。分离肽可包含氨基酸的L-或D-对映异构体形式或其组合。根据本发明的另一实施方案,分离肽可偶联至载体蛋白,或经由利用脂肪酸进行C末端酰胺化或N末端酰化(即,脂化)来修饰。当施加至皮肤及其伤口时,这些添加增强肽的生物活性。
根据本发明的某些优选实施方案,所述分离肽均在3位处包含赖氨酸。分离肽的具体实施方案包含SEQ ID NO:1、2、3、4、5、6和7,其均显示对细胞迁移的刺激活性并且影响伤口修复。
下文所显示的所衍生四肽适合式(I或V)-X1-K-X2,其中X1可选自E、Q和K;且X2可选自M、F、I、W、V和L。
SEQ ID NO. | HB NO. | 序列 |
1 | HB2233 | IEKM |
2 | HB2267 | VEKF |
3 | HB2270 | IEKI |
4 | HB2271 | IQKI |
5 | HB2272 | IKKW |
6 | HB2273 | IKKV |
7 | HB2274 | IKKL |
本发明的另一实施方案涉及包含药学上或美容学上可接受的载体和一种或多种前述肽的治疗或化妆品组合物。前述组合物可用于制造用于在使哺乳动物的皮肤伤口愈合的应用中使用的药剂或化妆品组合物。优选地,此种组合物中的肽的浓度在约0.1μg/mL至约500μg/mL或约0.1μg/mL至约20mg/mL的范围内。组合物的优选形式为气溶胶、乳液、液体、溶液、洗剂、乳膏、糊剂、油膏、粉剂、凝胶和泡沫剂(foam)。
另外,本发明的肽及包含其的组合物可提供纳入一般皮肤护理和化妆品制剂中的有用特性,所述制剂诸如多种皮肤化妆品、皮肤乳膏、洗剂、防晒液和治疗洗剂或乳膏,诸如用于激光手术后护理的抗痤疮制剂。
本发明还涉及使用前述组合物用于愈合哺乳动物的伤口的方法。通常,所述治疗方法需要向伤口和或炎症性病状、尤其皮肤(表皮)和相关黏膜组织的那些施用有效量的含肽组合物,持续有效时间量。此类伤口包括外科伤口、擦伤、水疱、烧伤、裂伤、溃疡、挫伤、皮疹、瘢痕、妊娠纹和由于老化和环境暴露的内在和外在效应导致的皮肤损害,包括起皱纹、皮肤下垂和光损害。炎症性皮肤病包括牛皮癣、异位性皮肤炎和酒糟鼻以及因去除毛发引起的炎症。
发明详述
趋化因子调节伤口愈合、炎症性/抗炎症性和血管生成/血管抑制活性。它们通过结合至白细胞上的受体的G蛋白偶合受体(GPCR)类别和目标组织中的细胞表面糖胺聚糖(GAG)来发挥其功能。趋化因子与GAG的结合是通过GAG上的带负电荷的链与趋化因子中的碱性残基团簇的相互作用生成的离子力来介导(Handel等人,2005)。在体内,情况更加复杂,并且已报导趋化因子通过产生固定化或趋触性梯度来起作用,梯度引导细胞至炎症部位的迁移(Proudfoot,2006)。GAG-趋化因子相互作用可在沿细胞外基质确立梯度中起关键作用且可促进趋化因子与其G蛋白质偶合受体的结合。GAG或硫酸肝素(HS)蛋白聚糖也可作为信号传导的功能性趋化因子共同受体起作用,从而导致形成GAG/趋化因子和趋化因子受体的三元复合物(Handel等人,2005)。关于具体趋化因子的研究已映射GAG与趋化因子的结合位点。在九种人类C-X-C趋化因子前体蛋白质(包括GRO-α前体(CXCL-1)、趋化因子2前体(CXCL-2)、趋化因子3前体(CXCL-3)、趋化因子4前体(CXCL-4)、趋化因子5前体(CXCL-5)、趋化因子6前体(CXCL-6)、IL-8前体(CXCL8)、趋化因子9前体(CXCL-9)、趋化因子11前体(CXCL-11))的保守GAG结合位点的一级氨基酸序列的密切检查中,我们发现尤其感兴趣的保守四肽区。此研究中所定义的保守四肽段定位于部分GAG结合区内。下文是选定人类C-X-C趋化因子前体的C末端序列的比对的示意性说明并且突出短四肽。比对是使用NCBI网站(ncbi.nlm.nih.gov)上关于的多个蛋白质序列比对的COBALT程序生成。仅显示比对中的每一趋化因子的C末端部分并且数字为序列中的残基的始端和末端。A.GRO-α前体(NCBI登录号P09341.1);B.趋化因子2前体(NCBI登录号NP_002080.1);C.趋化因子3前体(NCBI登录号NP_002081.2);D.趋化因子4前体(NCBI登录号P80162.4);E.趋化因子5前体(NCBI登录号NP_002985.1);F.趋化因子6前体(NCBI登录号NP_002984.1);G.IL-8前体(NCBI登录号);H.趋化因子9前体(NCBI登录号NP_002407.1);I.趋化因子11前体(NCBI登录号EAX05774.1)。
比对中显示在CXC趋化因子中高度保守的短四肽基序。*指示趋化因子的部分GAG结合位点。四肽显示保守骨架I-K-。除具有缬氨酸(V)的IL-8以外,所有其他IL-8在四肽基序的1位处具有异亮氨酸(I)且在3处具有赖氨酸(K)。因此,(I或V)-X1-K-X2式可用于代表所生成且在表1中所显示的四肽。值得注意的是,趋化因子的GAG结合区也参与二聚体形成,这是因为大部分CXC趋化因子可逆地以单体和二聚体形式存在,且因此募集特征将不仅受单体-二聚体平衡常数影响而且也受单体和二聚体与目标组织中的嗜中性粒细胞上的受体和与细胞表面及间隙空间上的GAG的结合相互作用影响(Gangavarapu等人,2012)。
下文所显示的所衍生四肽适合式I(V)-X1-K-X2,其中X1可选自E、Q和K;且X2可选自M、F、I、W、V和L。
SEQ ID NO. | HB NO. | 序列 |
1 | HB2233 | IEKM |
2 | HB2267 | VEKF |
3 | HB2270 | IEKI |
4 | HB2271 | IQKI |
5 | HB2272 | IKKW |
6 | HB2273 | IKKV |
7 | HB2274 | IKKL |
8 | HB2268 | KMG |
C-X-C趋化因子在其对许多细胞类型的趋化性活性方面众所周知。为评估最新衍生的四肽是否具有刺激角质细胞迁移的活性,使SEQ ID NO 1、2、3、4、5、6、7和8经受角质细胞刮伤测试,即充分接受的用于评估活性化合物诱导细胞迁移和体外伤口闭合的能力的测定。在不存在补充物以限制细胞增殖的无血清角质细胞生长培养基中实施实验。在所指示时间通过相位差显微术检查受伤区域。如表1中所显示,四肽显著诱导刮伤闭合。在20μg/ml下,与经PBS处理的伤口(以其为100%)相比,通过SEQ ID 1、2、3、4、5、6和7诱导的伤口闭合的百分比在165%至240%的范围内(表1)。随机生成的肽SEQ ID NO 8不诱导细胞迁移和刮伤闭合。为证实肽在针对刮伤闭合所测试的浓度下对角质细胞无毒,使所有肽经受MTT细胞毒性测试。在高达500ug/ml的浓度下孵育24小时后,任一肽对体外正常皮肤角质细胞均无细胞毒性。总而言之,与经PBS处理的对照细胞的百分比相比,使用四肽SEQ ID NO 1至7处理显著诱导正常人类表皮角质细胞至刮伤区域中的迁移,如通过7小时处理后受伤区域的闭合的百分比所指示。
血管生成(即从已存在血管网络形成新的毛细血管)是伤口修复的基本步骤。本发明中所生成的肽SEQ ID NO 1至7也刺激毛细血管形成。体外血管生成分析使用人类脐静脉内皮细胞(HUVEC)测量一系列导致形成新的毛细血管的事件。在诱导时,HUVEC进行迁移以对准,然后从个别细胞发芽。发芽事件导致形成新的毛细血管,其进一步发育以形成闭合多边形。最终,发育成复杂网状结构。人类组织蛋白酶抑制素(cathelicidin)肽LL-37是经充分研究的促进血管生成的实例。其在评估中用作阳性对照。新的毛细血管的发芽仅在使用LL-37处理3小时后即变得可视(表2)。在利用LL-37处理5小时后,形成闭合多边形。与LL-37相比,SEQ ID NO.1、2、3、4、5、6和7诱导HUVEC的类似变化,从而在3小时和5小时处理下导致新的毛细血管形成和复杂多边形结构(表2)。相比之下,随机生成的肽SEQ ID NO 8(KMG)和PBS在观测到LL-37和本发明肽的血管生成活性时不诱导这种变化(表2)。
众所周知革兰氏阳性细胞壁组分肽聚糖(PGN)刺激促炎性细胞因子表达。脂磷壁酸(LTA)是引起包括氧化氮合成酶(iNOS)、环氧合酶-2(COX-2)、IL-1β、TNF-α和IL-6上调的促炎性信号的浓度-和时间-依赖性增加的PGN中的关键分子(Lin等人,2010)。因此我们使用本发明肽预处理LTA并且然后评估在与人类皮肤角质细胞接触时的IL-6刺激活性。如表3中所显示,使用SEQ ID NO 1、2、3、4、5、6和7预处理LTA显著降低人类皮肤角质细胞培养物中的LTA刺激的IL-6表达的量,这表明所述肽可中和游离LTA的毒性效应。极为可能的是,四肽的带正电荷的残基结合至带负电荷的LTA,从而阻断LTA与其受体的相互作用。这是显著的,这是因为细菌细胞壁组分已参与炎症性皮肤病,诸如痤疮、酒糟鼻、异位性皮肤炎等。
细胞增殖的调节是伤口修复中的另一重要步骤。我们测试本发明肽对人类皮肤角质细胞的增殖活性。与刮伤测试、血管生成和阻断LTA诱导的IL-6表达中所测量的趋化性活性相比,本发明肽对角质细胞增殖的调节显示多样但中等的活性。SEQ ID NO 1(HB2233)显示对角质细胞增殖的抑制性活性,针对SEQ ID NO 3(HB2270)也观测到这种抑制性活性。SEQ ID NO 6似乎刺激角质细胞增殖,但这种活性仅为有限。对角质细胞增殖的抑制性活性提示我们测试TGF-β1表达,这是因为众所周知此生长因子抑制细胞增殖。如表4中所显示,SEQ ID NO 1和3二者在培养的角质细胞中诱导中等的TGF-β1表达水平。
由MatTek公司(Ashland MA)研发的SOR-300-FT是包括正常的人源性角质细胞和牛皮癣性纤维母细胞的高度分化的体外牛皮癣组织。在形态上,所述组织具有一致厚度并且其表达增加的过度增殖细胞水平以及促炎性标记(诸如牛皮癣素(psoriasin)、弹性蛋白酶抑制剂(elafin)、人类β-防御素-2(beta-defensin-2)和LL-37等)(Ayehunie等人,2012)。组织的促炎性条件提示我们测试本发明肽以检查其是否调节炎症性反应。由于所述组织模型的成本较高,选择代表性肽SEQ ID NO 1HB2233作为使用SOR-300-FT组织模型的概念研究的证据。使用HB2233以200μg/ml一式两份处理SOR-300-FT组织。研究总共12种与牛皮癣病状相关的基因标记。研究是同时采用卡泊三醇(calcipotriol)平行运行。qPCR分析显示,在处理72小时后,SEQ ID NO1(HB2233)使在发炎的牛皮癣皮肤中过度表达的LL-37的表达水平显著下调(3.7倍)(表5)。牛皮癣药物卡泊三醇显著下调HBD-2(9.0倍)和牛皮癣素(2.3倍)。HB2233和卡泊三醇下调负责牛皮癣皮肤中的角质细胞的过度增殖和早熟的Ki67表达。另外,SEQ ID NO 1(HB2233)也下调CXCL1(GROα)和CXCL5(ENA-78)表达,与正常健康皮肤相比,此二者的表达在牛皮癣皮肤中均显著上调(Ayehunie S.,2012),然而,卡泊三醇似乎不影响两种基因的水平。此明显表示HB2233可为经由与目前用于治疗炎症性皮肤病(诸如牛皮癣)的药物卡泊三醇不同的机制产生作用的新颖治疗剂。
为更好地理解相同肽影响正常健康皮肤组织的方式,我们将SEQ ID NO:1HB2233置于基因谱分析研究中,所述研究是由Sunny Biodiscovery(Santa Paula,CA)实施,使用自MatTek公司(Ashland,MA)购得的EPIDERMTM正常人类皮肤替代物。在以一式两份使用肽或水对照物处理24小时之前,先使皮肤替代物平衡过夜。在处理结束后,萃取RNA并且使其经受PCR阵列分析。如表6中所显示,SEQ ID NO1 HB2233刺激参与ECM合成的基因(胶原和整合素)。如人们所预期,它调节趋化因子(CXCL11和MAPK3等)和生长因子(TGF-β1和VEGF等)。基因谱分析研究支持体外观测到的本发明肽调节细胞增殖、血管生成和伤口愈合活性的活性。
使用标准Fmoc(9-芴基甲氧基羰基)固相化学合成本发明中所包括的所有肽。所述肽可使用标准氨基酸制备为酰胺化或游离酸序列形式。羧基末端的酰胺化可使得本发明肽对蛋白酶降解较不敏感并与游离酸形式相比增加其溶解度,从而提供升高的治疗效能。所述肽可包含L-或D-氨基酸对映异构体,包含一种对映异构体形式或两种形式的组合的残基。所述肽可在N末端和C末端两者上修饰。例如,据讨论N末端脂化或乙酰化可改善跨越皮肤的肽渗透而不会改变肽的生物活性功能(Samah,2011)。因此,肽也可被脂化,这可提供增强的皮肤渗透。可用于提供本发明化合物的C12-18脂质组分的饱和或不饱和脂肪酸的示例包括月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、肉豆蔻油酸、棕榈油酸、油酸和亚麻油酸。肽的羧基末端可使用酸(-COOH)或酰胺化(例如,-CONH2、-CONHR或-CONR2)修饰。羧基末端的酰胺化可使得本发明肽对蛋白酶降解较不敏感并与游离酸形式相比增加其极性,从而提供升高的治疗效能。此外,通常可被修饰的肽官能团包括羟基、胺基、胍盐、羧基、酰胺、酚、咪唑环或巯基。
肽也可偶联至可溶性或不可溶性载体分子以根据需要修饰其溶解度特性并且增加靶向组织中的肽的局部浓度。可溶性载体分子的实例包括(但不限于)聚乙二醇(PEG)与聚乙烯吡咯啶酮的聚合物;不可溶性聚合物的实例包括(但不限于)硅酸盐、聚苯乙烯和纤维素。肽可使用脂质体技术或经由奈米技术被微囊化以增强其稳定性并用于控制释放。对于以上方案,肽一般可使用所属领域技术人员所已知的任何方法诸如以下文献中所公开的方法产生:Merrifield(J Am Chem Soc.85:2149,1963);Carpino等人(J Org Chem.51:3732,1986);Merrifield等人(Anal Chem.38:1905,1966);或Kent等人[High YieldChemical Synthesis Of Biologically Active Peptides On An Automated PeptideSynthesizer Of Novel Design,IN:PEPTIDES 1984(Ragnarsson编辑)Almqvist andWiksell公司,Stockholm(Sweden),第185页至第188页],所述全部文献均以引用方式全文并入本文中。
本发明涉及使用上文所描述的肽(诸如)用于在制剂中或作为治疗剂的方法。这些方法可涉及使用单一肽或多个肽的组合。在某些情况下,本发明组合物可放置于置于皮肤的上、其中或其下方的装置内。此种装置包括以通过被动或主动释放机制接触皮肤或毛囊的方式释放所述物质的透皮贴剂、植入物和注射剂。在本文中所描述方法的用于递送肽的组合物可呈气溶胶、乳液、液体、洗剂、溶液、凝胶、微囊体、乳膏、糊剂、油膏、粉剂、泡沫剂或其他药学上可接受的制剂的形式。此外,肽可使用较少涉及的制剂(诸如去离子/蒸馏水、PBS或标准医用盐水溶液)递送。
所述制剂选择性地具有化妆品吸引力和/或包含其他试剂诸如类视色素、维生素C或可用作用于本发明肽的治疗作用的佐剂的其他肽。也可将抗生素添加至制剂中以避免感染,从而容许发生最大愈合进程。
所述制剂可包含蛋白酶抑制剂。可选择蛋白酶抑制剂以特异性靶向预期将降解所选择生物活性肽的蛋白酶;此选择将基于生物活性肽的长度和/或序列来决定。然而,蛋白酶抑制剂未必需要以任何具体方式选择;例如,在本发明中可采用包含两种或更多种抑制剂的蛋白酶抑制剂混合物(cocktail)。可将以下类型的蛋白酶抑制剂纳入本发明中:丝氨酸蛋白酶抑制剂、半胱氨酸蛋白酶抑制剂、天冬氨酸蛋白酶抑制剂、金属蛋白酶抑制剂、硫醇蛋白酶抑制剂和苏氨酸蛋白酶抑制剂。本发明中所用的蛋白酶抑制剂可为肽或蛋白质或化学物。此种抑制剂的非限制性实例为丝氨酸蛋白酶抑制剂(抗胰蛋白酶),其包括α-1-抗胰蛋白酶、补体1-抑制剂、抗凝血酶、α-1-抗胰凝乳蛋白酶、血纤维蛋白溶酶原活化剂抑制剂1和神经丝氨酸蛋白酶抑制剂(neuroserpin);或可用作用于本发明肽的治疗作用的佐剂的化学物,包括但不限于熊果酸和氨甲环酸(tranexamic acid)。
通常,药学上可接受的制剂将包括适于在人类皮肤上使用的任何载体。此种药学上和美容上可接受的载体包括乙醇、二甲亚砜、甘油、二氧化硅、氧化铝、淀粉和等效载体以及稀释剂。所述制剂任选地具有化妆品吸引力和/或含有其他试剂,诸如类视色素或可用作用于本发明肽的治疗作用的佐剂的其他肽。也可将抗生素添加至制剂中以避免感染,从而容许发生最大愈合进程。组合物中的肽的浓度可为约0.1μg/mL至约500μg/mL或约0.1μg/mL至约10%;然而,所采用的极限浓度可在这些范围外有所不同,这取决于伤口/组织情况的性质、本发明肽的生物活性和使用任何佐剂或技术以获得增强的组合物吸收。CTFACosmetic Ingredient Handbook第二版(1992)描述多种在皮肤护理行业中常用的非限制性化妆品和药物成分,其适宜用于本发明的组合物中。这些成分类别的示例包括:研磨剂、吸收剂、美容组分(诸如香味剂、颜料、着色剂(coloring/colorant)、精油、皮肤感知剂、收敛剂等(例如,丁香油、薄荷脑、樟脑、桉树油、丁香酚、乳酸甲酯、金缕梅精))、抗痤疮剂、抗结块剂、消泡剂、抗微生物剂(例如,丁基氨基甲酸碘丙酯)、抗氧化剂、粘合剂、生物添加剂、缓冲剂、增量剂、螯合剂、化学添加剂、化妆品杀生物剂、变性剂、药物收敛剂、外用止痛剂、成膜剂或材料、遮光剂、pH调整剂、推进剂、还原剂、螯合剂、皮肤漂白剂和美白剂(例如,氢醌、曲酸、抗坏血酸、抗坏血酸磷酸镁、抗坏血酸葡萄糖胺)、皮肤调理剂(例如,保湿剂)、皮肤安抚剂和/或愈合剂(例如,泛醇及其衍生物、芦荟、泛酸及其衍生物、尿囊素、没药醇和甘草酸二钾)、皮肤治疗剂、增稠剂和维生素及其衍生物。
可向人类和动物(包括所有哺乳动物)进行本发明肽和相关组合物的施用。也可与典型和/或实验材料(诸如组织移植物、皮肤替代物、组织培养产物和敷料)的组合施加。示例包括但不限于纱布(织造和非织造、经浸渍、不黏连、填塞、清创);压迫绷带和***;伤口填充物和清洁剂;接触层;胶原;羊膜;非细胞人类真皮;非细胞基质和组合产品;和多种常用敷料。
常用敷料的列表
通常,组合物可局部、经口、经皮、全身性或通过所属领域技术人员所已知的可用于向目标组织递送本发明肽的任何其他方法施用。例如,组合物也可以体外或离体方式施加至在培养中生长的细胞或患者移植物中。
本发明的组合物可包含一种或多种发挥皮肤护理活性的另外的试剂。除生物活性肽组分以外,本发明可包含其他活性剂,诸如透明质酸、烟碱酰胺、植烷三醇、金合欢醇、没药醇、水杨酸、视网醇、视网酸、α羟酸、抗坏血酸和多藻酸(alguronic acid)。预期某些另外的活性剂将与生物活性肽组分协同起作用,或将增强制剂的货架寿命。
此外,氨基酸的缩写遵循传统用法:
关于配制和施用药物的技术的细节可参见Remington’s PharmaceuticalSciences(Mack Publishing公司,Easton,Pa.)的最新版本。尽管局部递送是期望的,但存在其他递送方式,例如:经口、非肠道、气溶胶、肌内、皮下、经皮、髓内、鞘内、心室内、静脉内、腹膜内或鼻内施用。本发明可配制于多种载体媒介物中,例如,喷雾剂;气溶胶;油包水型乳液;水包油型乳液;面霜或体霜;防晒乳液或晒后乳液;或其他局部施用媒介物。另外,本发明的肽和包含其的组合物可提供纳入一般皮肤护理和化妆品制剂的有用特性,这些制剂诸如多种皮肤化妆品、皮肤乳膏、洗剂、防晒液和治疗洗剂或乳膏(诸如抗痤疮制剂)。
施加区域
本发明的肽可用于治疗皮肤的伤口。当表皮层自(诸如)裂伤、烧伤或水疱破坏时,发生皮肤和黏膜组织损害。损伤也可涉及压伤或挫伤,其涉及组织损害而无表皮的并发裂伤。皮肤感染以及某些慢性疾病(诸如癌症和自体免疫疾病)也可能需要表皮表面上的损伤。溃疡(诸如影响糖尿病的那些或与压褥疮相关的那些)为皮肤损伤的另一形式;这些伤口通常极难医治,发炎,易于感染,并需要一段时间的愈合过程。溃疡或其他类型的慢性伤口的持续性是由于参与愈合和新血管生成的细胞过程因受损血管生成能力而导致的失败所致。血管生成是因应缺氧或其他刺激物而形成新毛细血管网络(微血管)的过程(Folkman等人,1992)。所述过程涉及自缺氧内皮和支撑周细胞二者局部分泌诱导心血管的内皮增殖和发芽的血管生成因子。不足血管生成对受损伤口愈合和皮肤溃疡有所贡献(Galiano等人,2004)。伤口愈合失败也可为因伤口边界处的角质细胞不会迁移以闭合或覆盖痤疮的事实而不能使病灶部分地形成上皮的结果(Enoch和Price,2004)。部分地通过活化基底角质细胞来协调皮肤和黏膜伤口的愈合。在活化时,在称为上皮形成的过程中定位于伤口周边处的角质细胞迁移以在伤口上形成单层。已显示,在慢性伤口的不愈合边缘处的角质细胞为过度增殖的但不迁移的,且缺乏迁移导致不能形成上皮并在慢性溃疡的发病机制中起重要作用(Harsha等人,2008)。本发明也可用于治疗与皮肤和黏膜组织中的角质细胞相关的损害。术语“相关黏膜组织”是指以与皮肤类似的方式组织的任何组织并包含包括但不限于与口、鼻、喉、耳、***、生殖器和眼睛的眼睑结膜相关的内衬表面的上皮细胞/角质细胞。可影响这些组织并适于使用本发明肽治疗的伤口或病灶/损伤的示例为擦伤、水疱、烧伤、裂伤、刺伤、溃疡、挫伤、皮疹和瘢痕。外科后创伤也可利用所述肽来治疗。
另一种表皮损害形式较轻微且经过长时间产生,最终使皮肤功能受损,故称为老化皮肤。诱导皮肤老化的主要过程有两种;防晒皮肤的内在老化(自然老化)和在日光曝露区域的外在老化(光老化)。内在老化反映遗传背景且随时间变化。无论如何,老化皮肤具有以下一项或多项共通点:皱纹、细纹、色素沉着过度、红斑、损失光泽、平滑度、坚实度、肤色透明度和均匀度,以及毛孔外观的变化。除遗传倾向性以外,造成这些可见体征的原因也是由诸如紫外线(UV)和污染等环境刺激物的急性或慢性暴露诱导的各种组织学和细胞学变化。诸如起皱纹、干燥、变薄、下垂和对挫伤的较高敏感性等化妆品问题为除老化以外也可因长时间暴露于诸如紫外射线和污染等损害物而过早发生的表皮损害的常见表面体征。因此,所公开的肽可用于针对由内在和外在刺激物二者引起的老化皮肤相关问题,以防止并修复损害,从而再生健康皮肤组织,来逆转老化效应。以相关方式,可将肽施加至已因暴露至多种诸如日光等外来物而受到损害的组织。本发明也可在这些方面用作化妆品,以赋与更年轻外观和肌理。可使得本身未改变或经由化学修饰和/或特异化递送的短肽渗透穿过表皮,使其过程可对抗那些引起皮肤变薄、皱纹、脆弱和粗化/硬化的过程。由于角质细胞为表皮表面的主要组分且在老化和受损皮肤中减少,故预期通过肽的刺激来补充角质细胞即可逆转前述问题。
皮肤相当富有弹性,但其伸展的能力有限。妊娠纹或纹痕为色度不佳的皮肤上的一种结瘢形式。它们由撕裂真皮所造成,其可能随时间减少,但不能完全消失。它们先以微红或紫色纹形式出现,但往往逐渐褪色至较浅范围。妊娠纹常为与快速生长相关的皮肤快速伸展或快速重量损失的结果。妊娠纹会出现在完全未曾经历过显著或过度伸展或膨胀的身体部位的任何地方。大部分常见位置为腹部、***、上臂、腋下、背部、大腿、髋和臀。妊娠纹常为某些人生重要阶段(如***和怀孕)的激素变化所造成,但皮质类固醇治疗、肥胖、美容手术和大量健身可能导致妊娠纹。在皮质类固醇的作用下,角质细胞和纤维母细胞二者的生长会严重受损,且因此与正常皮肤相比,胶原I和III的合成以及纤维连接蛋白合成也显著减少高达90%以上(Rogalski等人,2002)。已显示高剂量皮质类固醇与抗血管内皮生长因子(抗血管生成)疗法的组合可使纹痕情况恶化且应加以避免(Wheeler等人,2012)。修复和恢复真皮/表皮部分中的角质细胞的功能可为妊娠纹矫正的关键。因此,促进刮伤闭合并刺激对伤口愈合所必需的血管生成的本发明肽对于妊娠纹的治疗而言为理想的。
角质细胞产生并分泌作为内源性抗生素和在皮肤先天性免疫***内作为信号传导分子起作用的抗微生物肽(AMP)。AMP为宿主先天性免疫防御***的关键组分并提供病原性微生物的第一道防线并将其杀死。另外,它们还通过各种机制调节并且改变宿主炎症性反应。然而,这些肽的异常表达与炎症性皮肤疾病的发病机制相关。目前研究暗示LL-37可在牛皮癣和酒糟鼻的发病机制中起重要作用。
牛皮癣为影响大约2%的一般人群的慢性炎症性皮肤疾病(Lowes等人,2007)。牛皮癣的特征在于Th1型T细胞和嗜中性粒细胞的累积、角质细胞过度增殖和分化以及增强的AMP表皮产生。在牛皮癣性病灶中,高度表达许多AMP,诸如组织蛋白酶抑制素(LL-37)、β-防御素、S100蛋白质、趋化因子、RNA酶7、溶菌酶、弹性蛋白酶抑制剂、嗜中性粒细胞明胶酶相关的脂质运载蛋白等等。特定而言,组织蛋白酶抑制素LL-37在牛皮癣中的炎症皮肤中过度表达,结合至自干燥细胞释放的细胞外自体DNA并将自体DNA转化成浆细胞样树突细胞的强效刺激物(Dombrowski等人,2012)。尽管关于LL-37在牛皮癣中的作用具有争议,但显然此肽诱导培养角质细胞中的促炎性细胞因子的角质细胞增殖和产生。除牛皮癣以外,LL-37目前已参与全身性红斑狼疮和类风湿性关节炎(RA)的发展。LL-37在全身性红斑狼疮患者的皮肤中高度表达(Sun等人,2011)。在RA中,嗜中性粒细胞刺激炎症并通过释放细胞毒性剂、AMP、蛋白酶和其他炎症性介体来损害关节中的组织。在动物模型中显示,如与健康关节相比LL-37在患有关节炎的大鼠的RA滑膜中和关节中强烈上调(Hoffmann等人,2012)。HB2233显著下调LL-37以及若干与炎症高度相关的其他因子的表达的观察结果表明,本发明肽可为包括但不限于牛皮癣、全身性红斑狼疮和类风湿性关节炎的炎症性病状的潜在治疗剂。
酒糟鼻为成人的一种最常见皮肤病。目前观念表明,诸如UV辐射、热、冷、压力、辛辣食物和微生物的已知临床诱发因子调节类Toll受体(Toll-like receptor)信号传导,诱导反应性氧物质,而且增强AMP和神经肽产生(Kenshi等人,2009;Yamasaki等人,2009)。过量的呈LL-37形式的组织蛋白酶抑制素报导于酒糟鼻中,酒糟鼻似乎由通过TLR进行的先天性免疫模式识别的异常功能、以及处理hCAP18的蛋白酶造成(Yamasaki等人,2007;2011)。与牛皮癣和全身性红斑狼疮类似,已推测在酒糟鼻中LL-37的过量存在使能够通过浆细胞样树突细胞和角质细胞二者识别自体核酸,所述两种细胞可加剧炎症,从而通过容许自体炎症性信号传导而对疾病有贡献(Gilliet等人,2008;Ganguly等人,2009)。通过本发明肽下调SOR-300-FT皮肤组织中的LL-37支持用于改良酒糟鼻中的LL-37相关性炎症性病状的有希望且潜在有用的治疗。
除炎症性皮肤病以外,高含量的LL-37也与若干侵袭性实体肿瘤类型相关。显示LL-37在人类***肿瘤中随Gleason评分增加并在骨转移中逐渐过度表达(Jonathan等人,2011)。在卵巢癌(Coffelt等人,2008)、乳癌(Heilborn等人,2005)和肺癌(von Haussen等人,2008)的癌中得到类似临床观察结果。尽管LL-37通常通过嗜中性粒细胞蛋白酶3自其前体人类组织蛋白酶抑制素抗微生物蛋白质-18(hCAP-18)裂解而变得活化,但有证据表明癌症细胞也产生酶来以蛋白水解方式裂解其所分泌的与嗜中性粒细胞无关的hCAP-18(等人,2001)。这可解释癌症中升高的LL-37含量。尽管LL-37参与癌症仍有待阐明,但LL-37增强增殖、血管生成、免于凋亡和上皮间质转换的特性均可用作癌症的标志且可由转化细胞/恶性细胞利用以促进肿瘤生长和转移。通过本发明肽(例如HB2233)下调LL-37可提供减少LL-37含量,从而防止癌细胞扩散的有效方式。可与癌症药物组合进一步增强潜在益处。
经细菌的感染可造成败血症并导致败血性休克,其特征在于难治性低血压和最终多器官衰竭和死亡(Ulevitvh等人,1995)。革兰氏阳性败血症已经识别为重要临床病状(Ulevitvh等人,1995)。其主要致病因子为***的细胞壁组分,如肽聚糖(PGN)和脂磷壁酸(LTA)。除败血性休克以外,LTA也是其他炎症性病状的主要致病因子。异位性皮肤炎(AD)为常见慢性炎症性皮肤疾病。未完全理解AD的发病机制并且组织蛋白酶抑制素(LL-37)表达水平及其与湿疹的疾病严重性的关联一直存在争议。AD患者对葡萄球菌皮肤感染特别敏感,葡萄球菌皮肤感染与其皮肤病的恶化相关。尽管葡萄球菌细菌可使AD恶化的机制尚不清楚,但在通过角质细胞或免疫细胞的直接感染或与细菌组分或碎片的相互作用后的细胞因子产生似乎起重要作用(Bieber等人,2008)。金黄色葡萄球菌(S.aureus)感染为皮肤炎症的已知诱发物且可因细菌或细菌产物的直接侵袭而调节免疫反应。研究指示AD皮肤病灶上高含量的金黄色葡萄球菌LTA(Travers等人,2010)。发现源自AD病灶的洗涤流体诱导鼠类骨髓源DC产生IL-1β、IL-6、IL-10和肿瘤坏死因子-α(Travers JB等人,2010)。本发明肽显示体外与葡萄球菌LTA的高结合水平,并且这种活性可提供用于中和在感染或抗生素治疗期间自革兰氏阴性细菌释放的LTA或LPS的毒性效应以改善与败血性休克和AD皮肤相关的病状的有希望治疗。
本发明肽调节角质细胞上的TGF-β(转化生长因子β)表达的可能性令人特别感兴趣。TGF-β为调控细胞增殖、分化、凋亡、基质重塑、黏着、侵袭和迁移的多效性细胞因子/生长因子。通常,TGF-β1可由许多不同细胞类型来产生。已发现所有TGF-β同种型刺激通过纤维母细胞进行的细胞外基质蛋白质的合成和周转。
毛囊为皮肤的整体组分,并且每一根毛发为毛囊的角质化产物。每个和每一个毛囊经历如下活动周期:毛发生长至最大长度,然后生长停止,并且毛发脱落并置换。毛发生长周期的各阶段已描述为毛发生长初期,其是长生长时期;毛发生长中期,其是自生长至静止的过渡时期,持续2周至4周;毛发生长终期,其是不活动时期,持续2个月至4个月。尽管缺少在人类中的直接证据,但对小鼠的研究表明,抑制角质细胞增殖和诱导TGF-β1产生与毛发生长中期消退直接有关(Foitzik等人,2000)。在体外观察到,分离的器官培养的大鼠和人类毛发生长初期的毛囊的生长受TGF-β1抑制,此在若干方面中类似于毛发生长中期样转化的早期。SEQ ID NO 1HB2233抑制角质细胞生长和调节TGF-β1表达的活性可表明,本发明肽可能可用作治疗剂来去除不期望毛发。另外,TGF-β的上调也通过下调MITF以及黑色素生成基因(从而导致灰发)而与黑色素细胞未成熟有关(Nishimura等人,2010)。因此,本发明肽也具有用于诸如暗斑脱色或皮肤美白等应用的极大可能性。
皮赘(ST)、软纤维瘤、纤维性上皮息肉或垂疣为描述常见良性皮肤病状的所有替代术语,所述常见良性皮肤病是由自周围皮肤突出的一点皮肤组成。组织学上,ST为温和地覆盖在棘皮症表皮上的息肉状病灶,即呈现轻度慢性炎症和无力真皮的松散的水肿纤维小管核。皮赘被视为皮肤的最常见纤维病灶。尽管未完全理解确切病因,但已报导与肥胖、糖尿病、摩擦、肢端肥大症、器官移植、人类***状瘤病毒和其他病状的关联(Zaher等人,2007)。已证明生长因子和激素以及其受体在皮赘形成中起重要作用(Safoury等人,2010ab)。事实上皮赘是由刺激表皮角质细胞和真皮纤维母细胞增殖的因子造成,阻抑细胞增殖的化合物(诸如本发明肽)可潜在地用于减缓进程并防止形成皮赘。
本发明包括以下实例以展示本发明的某些优选实施方案。
实施例
实施例1:刺激细胞迁移和刮伤闭合的肽的鉴别
使人类皮肤角质细胞(ATCC CRL-2404)在补充有5ng/ml人类重组上皮生长因子(EGF)的无血清角质细胞生长培养基(Life Technologies,Grand Island,N.Y.)中生长。将所述细胞接种至12孔板上并使其达到100%融合。使细胞单层饥饿24小时,然后使用P200(200μl)移液管吸头制备刮伤。洗涤刮伤并在时间0处进行拍照。添加肽达20μg/ml的最终浓度。将细胞保持于孵育器中37℃、5%CO2下,孵育器具有>90%湿度,当在室温下在短时间内捕获图像时除外。在7小时至8小时处理后进行刮伤闭合并且结果显示于表1中。
表1.如使用角质细胞刮伤闭合评估细胞迁移的刺激。在7小时处理后,经PBS处理的闭合区域的百分比取为100%,计算经肽处理的伤口闭合并如相对于经PBS处理的伤口来呈现。
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实施例2:对正常人类皮肤角质细胞的细胞毒性
为了确保肽对细胞无细胞毒性,将正常人类表皮角质细胞接种至96孔板。在37℃下在5%CO2的存在下孵育所述板,以使得细胞生长至>95%融合。将肽稀释至储备溶液中达50μg/ml、100μg/ml、200μg/ml和500μg/ml的浓度。将细胞培养基使用包含多种浓度的肽的新鲜培养基置换,然后在37℃和5%CO2下孵育24小时。在处理结束时,使用自ATCC(Manassas VA)购得的MTT测定试剂盒测量细胞活力。结果显示于表1中。在50μg/ml至500μg/ml的浓度下肽不改变细胞活力,如使用MTT测定所测量。
实施例3:刺激血管生成的肽的鉴别
使用自Millipore购得的体外血管生成测定试剂盒实施血管生成测定。简而言之,根据制造商说明书使用ECMATRIXTM溶液制备基质层。在补充有0.1mg/ml的肝素(Sigma-Aldrich)、30ug/ml的ECGS(Sigma-Aldrich)和10%胎牛血清(ATCC,Manassas,VA)的完全F12K培养基(ATCC,Manassas,VA)中培养人类脐静脉内皮细胞(HUVEC)(ATCC,Manassas,VA)。收获细胞并且将其再悬浮于完全培养基中。在96孔板中将肽与细胞以每孔大约5×103个至1×104个细胞混合,然后将细胞接种至聚合ECMATRIXTM溶液的表面上。将板在30℃、5%CO2下孵育长达9小时至12小时。在倒置光学显微镜下定期检查管形成并且以3小时和5小时间隔获取图像并如下文所显示向每一图案指定数值。
图案 | 值 |
个别细胞,充分分离 | 0 |
细胞开始迁移并自身排列 | 1 |
毛细血管可见,无发芽 | 2 |
新毛细血管的发芽可见 | 3 |
闭合多边形开始形成 | 4 |
复杂网状结构生成 | 5 |
如表2中所显示。SEQ ID NO 1至7显著刺激人类脐静脉内皮细胞上的毛细血管形成。如所预期,将LL-37用作阳性对照并且它也刺激血管生成。将PBS用作阴性对照并且细胞开始迁移并自身排列,但在5小时处未形成发芽或闭合多边形。
表2.新毛细血管形成的诱导的结果。≥3的值视为血管生成的显著诱导
*:显著
实施例4:阻断LTA诱导的IL-6表达的肽的鉴别
金黄色葡萄球菌LTA在人类表皮角质细胞上诱导IL-6刺激。在无血清角质细胞培养基中使人类角质细胞生长至>80%融合。将金黄色葡萄球菌LTA 10ug/ml与每种肽(50μg/ml)一起在室温下预孵育30分钟,然后将混合物转移至角质细胞培养物中。使处理持续24小时。去除悬浮液。在短暂旋转以去除可能细胞碎片后,根据制造商说明书使用自CellSciences(Canton,MA)购得的ELISA试剂盒使悬浮液经受IL-6测试。如表3中所显示,SEQ ID NO 1-7明显中和或拮抗LTA刺激人类皮肤角质细胞上的IL-6表达的效应。
表3.阻断人类皮肤角质细胞上的LTA诱导的IL-6表达
*:显著
实施例5:肽调节细胞增殖和人类皮肤角质细胞上的TGF-β表达的鉴别。
使正常人类皮肤角质细胞(ATCC CRL-2404)生长在补充有5ng/ml人类重组上皮生长因子(EGF)(Life Technologies,Grand Island,N.Y.)的无血清角质细胞生长培养基中。每天用显微镜检查所述细胞。当培养物变成50%至75%融合时,抽吸板中的培养基并添加0.25%胰蛋白酶/EDTA。当细胞变成圆形并分离时,通过添加新鲜培养基来中和胰蛋白酶。然后对细胞进行离心并将沉淀物再悬浮于新鲜培养基中。使用血球计计数细胞悬浮液,并通过将100μl的细胞悬浮液添加至每个孔中来将细胞总数调整至每孔约500个至1000个细胞。通常,使用中心60个孔并且使用新鲜培养基填充外边各孔以使蒸发降至最低。当在6小时至8小时孵育后细胞在每个孔中附着时,一式三份添加100μl包含PBS的新鲜培养基或2×期望浓度的肽。然后将微板在37℃和5%CO2下孵育48小时至72小时。
在孵育结束时,根据制造商说明书使细胞经受CYTOSCANTM SRB细胞细胞毒性测定(GBiosciences,St.Louis,MO)。简而言之,将细胞固定,然后进行磺酰罗丹明B(SRB)染色。在大量洗涤后,使用增溶缓冲液使颜色增溶。使用微板读数器在565nm下测量吸亮度。表5中所显示的结果为一式三份处理的平均值且超过对照的±10%的值视为显著。
由Sunny Biodiscovery Lab(Santa Paula,CA)实施TGF-β刺激。简而言之,使正常新生儿人类表皮角质细胞在cellnTec角质细胞生长培养基(Switzerland)中生长。根据培养基供应商,培养基不含TGF-β。实验当日,更新生长培养基并将细胞用50μg/ml的肽一式三份处理72小时。在处理结束时,将悬浮液去除,活化并使用LEGEND MAXTM总TGF-β1ELISA试剂盒(Biolegend,Sam Diego,CA)量化。
表4.本发明肽对细胞增殖和人类皮肤角质细胞上的TGF-β产生的活性
*:中等效应
实施例6:代表性肽对SOR-300-FT人类牛皮癣组织构建体的效应。
将SOR-300-FTTM组织转移至包含0.9ml的预升温测定培养基的6孔板中并平衡至标准培养条件(37℃,5%CO2),持续1小时。在1小时平衡后,如以下用新鲜培养基再喂养所述组织:1)对于24小时时间点,用0.9ml的培养基喂养组织,且2)对于>24小时的时间点,通过将细胞培养***物(insert)置于洗涤器(零件号EPI-WSHR,MatTek公司)顶部来用5ml的培养基供料组织。接着,将50μl的测试品局部施加至牛皮癣性组织(n=3),且将测试品以由赞助商选择的3个浓度添加至培养基中。在24小时和48小时时间:a)用300μL至400μL的PBS将组织局部冲洗3X,b)用无菌钳紧密固持包含所述组织的***物且通过将***物浸渍于PBS中来温和地冲洗测试品并从***物倾倒出培养基,并且c)在冲洗和倾倒后立即将新鲜测试品再施加至组织(局部地50μL)。在t=72小时处实施分析(3X重复施加)。使用Qiagen RT2第一链试剂盒(目录编号330401)生成cDNA。使用Qiagen RT2SYBR Green qPCR Mastermix(目录编号330502)和Qiagen RT2引物测量相对基因表达。使用Bio-Rad CFX软件实施分析。
表5.在HB2233和卡泊三醇对SOR-300-FT组织处理后基因表达水平的倍数变化
实施例7:对正常人类皮肤替代物的基因谱分析。
使用由Sunny Biodiscovery公司(Santa Paula,CA)构建的PCR阵列分析84个编码细胞外基质和粘着分子的基因。简而言之,EPIDERMTM皮肤替代物(目录编号EPI-212)从MatTek(Ashland,MA)获得并根据制造商说明书处置。在平衡过夜后,改变培养基并将HB2233(330ug/ml)或水对照一式两份施加于皮肤组织上并允许处理持续24小时。在处理结束时,收集组织并将其保存在RNAlater溶液(Ambion,Austin,TX)中。萃取RNA并利用Illustra mini RNAspin试剂盒(目录编号95017-489,GE Healthcare,Piscataway,NJ)进行纯化。使用Agilent HP-8452A二极管阵列分光亮度计在260nm和280nm下评估经纯化的总RNA。在样品间平衡RNA的浓度,且通过实时定量PCR使用BioRad iCycler iQ检测***、使用PCR阵列PAHS-121A并使用第一链合成试剂盒测量感兴趣基因的表达。来自Qiagen的SYBRGreen主混合物和PCR电泳条件,在使用RT2Profiler PCR阵列数据分析3.5版本软件将基因表达对5种管家基因标准化后,使用效率ΔΔCt方法用于结果量化。若表达水平适当地高(小于30个检测循环)且在每一个一式两份系列中调节为1.5或更多,则认为有差别地表达基因。
表6.对经HB2233处理的EPIDERMTM皮肤组织相对于经水处理对照的选定基因表达谱分析,以倍数变化表示
根据本公开无需过多实验即可获得并实施本文所公开和要求保护的所有组合物或方法。尽管已根据优选实施方案描述本发明的组合物和方法,但所属领域技术人员应明了,可改变所述组合物和/或方法以及本文所述的方法的步骤或步骤顺序,此并不背离本发明的概念、精神和范围。更具体而言,应明了,某些在化学和生理上均相关的试剂可代替本文所述的试剂,同时可达成相同或相似的结果。所属领域技术人员所了解的所有此种类似的替代和修改被视为属于本发明的范围内。
本申请案中所确认的所有专利和出版物均以引用方式全文并入本文中。
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Claims (22)
1.一种分离的四肽,其具有伤口修复和再生活性,其中所述四肽为SEQ ID NO:1(IEKM)、SEQ ID NO:3(IEKI)、SEQ ID NO:4(IQKI)、SEQ ID NO:5(IKKW)、SEQ ID NO:6(IKKV)或SEQ ID NO:7(IKKL),并且其中C-末端为游离酸形式以及N-末端被脂化或者N-末端未被修饰。
2.根据权利要求1所述的四肽,其包含L-氨基酸对映异构体。
3.一种组合物,其包含至少一种根据权利要求1至2中任一项所述的四肽和药学上可接受的载体。
4.根据权利要求3所述的组合物,其中所述四肽以在0.1μg/mL至20mg/mL的范围内的浓度存在。
5.根据权利要求4所述的组合物,其中所述四肽以在0.1μg/mL至500μg/mL的范围内的浓度存在。
6.根据权利要求3所述的组合物,其中所述组合物为液体。
7.根据权利要求3所述的组合物,其中所述组合物为溶液。
8.根据权利要求3所述的组合物,其中所述组合物呈气溶胶、乳液、洗剂、凝胶、微囊化、乳膏、糊剂、油膏、粉剂或泡沫剂的形式。
9.根据权利要求3所述的组合物,其中所述组合物纳入适于施加至皮肤表面或施加于皮肤组织下方的装置中。
10.一种用于在以治疗有效量施加有效时间量时为哺乳动物愈合伤口或治疗炎症性皮肤病的组合物,其中所述组合物包含药学上可接受的载体和至少一种根据权利要求1至2中任一项所述的四肽。
11.根据权利要求10所述的组合物,其中所述伤口影响所述哺乳动物的皮肤或相关黏膜组织。
12.根据权利要求10所述的组合物,其中所述炎症性皮肤病影响所述哺乳动物的皮肤或相关黏膜组织。
13.根据权利要求11所述的组合物,其中所述伤口是由于擦伤、水疱、烧伤、裂伤、溃疡、挫伤、皮疹、膨胀纹、瘢痕、妊娠纹或老化的效应所致。
14.根据权利要求11所述的组合物,其中所述伤口是由于环境暴露的效应所致。
15.根据权利要求12所述的组合物,其中所述炎症性皮肤病是由于牛皮癣、异位性皮肤炎和酒糟鼻、去除毛发或去除皮赘所致。
16.根据权利要求3至9中任一项所述的组合物在制备用于皮肤护理治疗的药剂中的用途。
17.根据权利要求3至9中任一项所述的组合物在制备用于化妆品产品中的用途。
18.根据权利要求1至2中任一项所述的四肽或权利要求3至9中任一项所述的组合物在制备用于治疗皮肤或相关黏膜组织的伤口的药剂中的用途。
19.根据权利要求1至2中任一项所述的四肽或权利要求3至9中任一项所述的组合物在制备用于治疗皮肤或相关黏膜组织的炎症性病状的药剂中的用途。
20.根据权利要求18所述的用途,其中所述伤口是由于擦伤、水疱、烧伤、裂伤、溃疡、挫伤、皮疹、膨胀纹、瘢痕、妊娠纹或老化的效应所致。
21.根据权利要求18所述的用途,其中所述伤口是由于环境暴露的效应所致。
22.根据权利要求19所述的用途,其中所述炎症性病状是由于牛皮癣、异位性皮肤炎和酒糟鼻、去除毛发或去除皮赘所致。
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PCT/US2014/037978 WO2014200651A1 (en) | 2013-06-14 | 2014-05-14 | Tetrapeptides derived from human c-x-c chemokines useful for treatment of various skin conditions |
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CN110302088A (zh) * | 2019-04-29 | 2019-10-08 | 杭州肽佳生物科技有限公司 | 一种包含修饰芋螺肽的化妆品组合物 |
KR20220130144A (ko) * | 2020-01-21 | 2022-09-26 | 에이에스씨 리제니티 리미티드 | 피부의 외관 및 재생을 개선시키는 신규한 펩티드를 포함하는 국소 투여용 화장 제형 |
PL245202B1 (pl) | 2020-03-06 | 2024-06-03 | Gdanski Univ Medyczny | Lipopeptydowe koniugaty i ich sole, sposób wytwarzania lipopeptydowych koniugatów i ich soli, kompozycja farmaceutyczna zawierająca lipopeptydowy koniugat i jego sole do leczenia ran przewlekłych |
WO2022098051A1 (ko) | 2020-11-05 | 2022-05-12 | 한국생명공학연구원 | 항염 및 조직 재생작용을 갖는 신규 펩타이드 |
CN113698452B (zh) * | 2021-08-23 | 2023-08-18 | 四川丽妍工坊生物科技有限公司 | 一种促皮肤修复肽、制备方法及其应用 |
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