CN117295512A - 用于改善瘢痕和瘢痕瘤的包含zag衍生的肽的组合物 - Google Patents
用于改善瘢痕和瘢痕瘤的包含zag衍生的肽的组合物 Download PDFInfo
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- CN117295512A CN117295512A CN202180097683.5A CN202180097683A CN117295512A CN 117295512 A CN117295512 A CN 117295512A CN 202180097683 A CN202180097683 A CN 202180097683A CN 117295512 A CN117295512 A CN 117295512A
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Abstract
本发明涉及锌‑α‑2‑糖蛋白(ZAG)衍生的肽及其用途。根据本发明的ZAG蛋白衍生的肽可用于通过抑制细胞迁移和减少与瘢痕形成相关的RNA和蛋白质的表达来预防、治疗或改善瘢痕。
Description
技术领域
本发明涉及包含具有预防、治疗或改善瘢痕效果的肽的组合物。
更具体地,本发明涉及用于预防、治疗或改善增生性瘢痕或瘢痕瘤的药物或化妆品组合物,其包括由衍生自锌-α-2-糖蛋白(ZAG)蛋白的氨基酸序列组成的肽。
背景技术
瘢痕是被疾病或外界刺激损伤的愈合皮肤的痕迹。一般来说,当皮肤上/皮肤中出现一定程度或更严重的创伤时,随着组织的修复,会形成瘢痕。当结疤过程中出现问题时,瘢痕可能会过度生长。在这种情况下,随着时间的推移,瘢痕可能不会恢复到最初的皮肤状态,从而降低生活质量,并引起不适症状。
当皮肤发生深度损伤时,过量的胶原会在受影响的区域积累,导致比正常情况下更大的瘢痕。在此过程中形成的瘢痕被归类为增生性瘢痕或瘢痕瘤。
增生性瘢痕一般是由于受影响的区域中胶原的过度积累引起的,随着瘢痕变得比受影响的区域尺寸更大,颜色变深,突出,形状变软,伤口愈合。这些增生性瘢痕发生在创伤后的短时间内,并可能随着时间的推移而改善。此外,瘢痕仅出现在伤口内,具有很高的结疤频率,并且在颜色上与皮肤相似。
另一方面,瘢痕瘤是一种在伤口愈合过程中纤维组织生长异常致密的疾病,并且是由于调节伤口愈合的功能中的问题而发生的。瘢痕瘤最显著的特征是厚厚的真皮层,其中胶原纤维束又厚又多,所以除了胶原外,还沉积了过量的蛋白聚糖。瘢痕瘤皮肤带来了美容问题,因为它不仅扩散到伤口区域,还扩散到周围区域,并且当瘢痕瘤出现在油性区域如面部或关节时,它们可能会干扰关节或肌肉的运动。
治疗增生性瘢痕或瘢痕瘤的方法包括类固醇、激光、冷冻疗法、手术切除、微针疗法、化学剥脱等,使用类固醇和激光的治疗是最常用的。类固醇具有抑制纤维合成、减少瘢痕区域炎症和抑制增加瘢痕尺寸的物质产生的功能。然而,要达到这些效果,必须使用高浓度的类固醇,这可能会在使用过程中引起疼痛,并在长期使用时产生副作用,如皮肤萎缩、血管舒张等。使用激光的治疗包括一种使瘢痕变浅的方法,因为在表面结痂后表皮变薄,并在手术后脱落。然而,手术后表皮变薄,因此可能成为敏感皮肤,这导致水分控制和免疫功能降低,并对即使很小的刺激也有强烈的反应。
同时,锌-α-2-糖蛋白(ZAG)蛋白具有改善干皮病或皮肤屏障功能障碍的功能,并且通过促进连丝蛋白的表达,其可以治疗由连丝蛋白(filaggrin)减少引起的诸如干皮病、皮肤屏障功能障碍和炎症反应等疾病。
在本发明中,证实了ZAG蛋白可以调节胶原I、III和转化生长因子-β(TGF-β)的RNA表达以及胶原I、III、TGF-β和pSMAD2/3的蛋白表达,从而抑制瘢痕的形成,所述胶原I、III、TGF-β和pSMAD2/3参与瘢痕的形成,优选增生性瘢痕或瘢痕瘤。
因此,本发明提供了具有预防、治疗或改善瘢痕(优选增生性瘢痕或瘢痕瘤)的效果的ZAG蛋白衍生的肽。此外,本发明提供了具有预防、治疗或改善瘢痕(优选增生性瘢痕或瘢痕瘤)的效果的ZAG蛋白衍生的肽的新发现的核心活性位点(即片段)。
[相关技术文件]
[专利文件]
1.韩国专利No.10-2166543
发明内容
[技术问题]
本发明涉及提供能够预防、治疗或改善瘢痕的锌-α-2-糖蛋白(ZAG)蛋白衍生的肽。
更具体地,本发明旨在提供ZAG蛋白衍生的肽的新发现的活性位点,其抑制由纤维过度形成引起的增生性瘢痕或瘢痕瘤中细胞的过度增殖和迁移,并且还抑制如胶原I、胶原III和TGF-β等的RNA表达以及胶原I、III、TGF-β和pSMAD2/3的蛋白表达,并提供包含其的组合物。该组合物可用作药物或化妆品组合物,用于预防、治疗或改善瘢痕,优选增生性瘢痕或瘢痕瘤。
[技术方案]
根据本发明的一个方面,本文提供了一种用于预防或治疗瘢痕的药物组合物,其包含ZAG蛋白衍生的肽。
根据本发明的另一方面,本文提供了一种用于改善瘢痕的化妆品组合物,其包含ZAG蛋白衍生的肽。
[有益效果]
根据本发明的ZAG蛋白衍生的肽可以通过抑制瘢痕中细胞的过度增殖和迁移而对瘢痕的形成具有抑制作用,所述瘢痕优选为由过度形成纤维引起的增生性瘢痕或瘢痕瘤。
此外,ZAG蛋白衍生的肽可以通过抑制RNA和蛋白在瘢痕中过表达而具有预防、治疗或改善瘢痕的效果,所述瘢痕优选为增生性瘢痕或瘢痕瘤。
特别地,在本发明中,通过最小化肽的长度,可以降低组合物的生产成本,所述组合物包括包含所选ZAG蛋白的核心活性位点的肽作为活性成分。
附图说明
图1是显示当用Z1至Z18肽处理时,通过CCK-8检测证实人真皮成纤维细胞(HDF)和瘢痕瘤成纤维细胞(KF)增殖的结果的图。
图2是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z16处理时,对细胞迁移的抑制作用的图。
图3是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z16处理时,对RNA和蛋白表达的作用的图。
图4是显示当另外合成寡肽,然后用寡肽处理HDF和KF以鉴定ZAG衍生的肽的核心活性位点时,通过CCK-8检测证实细胞增殖的结果的图。
图5是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z15聚体_1至Z15聚体_4处理时,对细胞迁移的抑制作用的图。
图6是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z15聚体_1至Z15聚体_4处理时,对RNA和蛋白表达的作用的图。
具体实施方式
[最佳模式]
本发明人已经在锌-α-2-糖蛋白(ZAG)蛋白中发现了有效抑制瘢痕形成或预防、治疗或改善瘢痕的肽。
因此,本发明提供了ZAG蛋白衍生的肽在制备用于预防、治疗或改善瘢痕的药物或化妆品中的用途。
此外,本发明提供了用于预防或治疗瘢痕的药物组合物,其包括作为活性成分的ZAG蛋白衍生的肽,以及用于改善瘢痕的化妆品组合物,其包括作为活性成分的ZAG蛋白衍生的肽。
此外,本发明提供了一种预防、治疗或改善瘢痕的方法,该方法包括:向受试者施用治疗或生理有效量的ZAG蛋白衍生的肽。
在本发明中,术语“瘢痕”是指替代被损伤或疾病破坏的正常组织的纤维组织。皮肤外层的损伤通过重建组织而愈合。在这种情况下,瘢痕形成可能是最小的。然而,当皮肤下的厚层组织受损时,重建变得更加复杂。在其中积聚了胶原纤维(一种体内自然产生的蛋白质),这通常会导致明显的瘢痕。
根据一个示例性实施方案,瘢痕可包括增生性瘢痕、瘢痕瘤、萎缩性瘢痕或其组合。
在本发明中,术语“增生性瘢痕”是指当胶原在受影响的区域过度积累并残留在病变边界内时出现的凸起的瘢痕。一般来说,增生性瘢痕在初次损伤后会自然退化。增生性瘢痕是坚硬、凸起、呈红色、发痒、触痛和收缩的。临床上和组织学上,增生性瘢痕和瘢痕瘤非常相似;然而,增生性瘢痕通过挤压瘢痕边缘而扩大,而瘢痕瘤则渗入周围组织。随着时间的推移,增生性瘢痕会成熟并变平。
在本发明,术语“瘢痕瘤”是指一种在伤口愈合过程中纤维组织生长异常致密的疾病,并且是由于调节伤口愈合的功能中的问题而发生的。纤维组织突出于皮肤表面,并延伸至最初受影响的区域的边界之外。瘢痕瘤是永久性的,不会随着时间的推移而退化。瘢痕瘤往往不美观,并可能涉及疼痛。
在本发明中,“萎缩性瘢痕”是平的并压在周围皮肤下。它通常很小,通常是圆形的,具有锯齿或倒置的中心。萎缩性瘢痕的形成可能由手术、外伤、痤疮和水痘引起。
在本发明中,瘢痕可以优选是由纤维过度形成引起的增生性瘢痕或瘢痕瘤。
本发明中使用的术语“ZAG蛋白衍生的肽”是指在ZAG蛋白的氨基酸序列中显示出对瘢痕(优选增生性瘢痕或瘢痕瘤)形成抑制作用的活性肽。
根据一个示例性的实施方案,“ZAG蛋白衍生的肽”可以是由10聚体或以上且30聚体或以下的氨基酸序列组成的肽,其包括ZAG蛋白的片段。包含在“ZAG蛋白衍生的肽”中的ZAG蛋白片段可以例如由构成ZAG蛋白的氨基酸序列中的10聚体至30聚体、10聚体至25聚体、10聚体至20聚体和10聚体至15聚体的连续氨基酸序列组成。
根据一个示例性实施方案,ZAG蛋白的片段可以由构成ZAG蛋白的氨基酸序列中的10聚体至30聚体的连续氨基酸序列组成。
根据一个示例性实施方案,ZAG蛋白的片段可以由选自SEQ ID NOS:1至18的任意一种氨基酸序列组成。
根据一个示例性实施方案,ZAG蛋白的片段可以由选自SEQ ID NOS:19至22的任意一种氨基酸序列组成。
在本发明中,在某些描述中,“ZAG蛋白衍生的肽”可以与“ZAG蛋白的片段”互换使用。例如,ZAG蛋白衍生的肽可以由选自SEQ ID NOS:1至18的任意一种氨基酸序列组成。或者,ZAG蛋白衍生的肽可以由选自SEQ ID NOS:19至22的任意一种氨基酸序列组成。
本发明的一个实施方案公开了一种ZAG蛋白衍生的肽,其对瘢痕(优选增生性瘢痕或瘢痕瘤)的形成表现出抑制作用。本发明的“ZAG蛋白衍生的肽”可以是表1所示的ZAG蛋白衍生的肽Z1至Z18之一(分别为SEQ ID NOS:1至18),但本发明不限于此。这些肽可能对瘢痕形成有抑制作用。特别地,可以看出,与ZAG蛋白相比,ZAG蛋白衍生的肽Z1、Z2、Z8至Z10、Z15和Z16对增生性瘢痕或瘢痕瘤的形成具有更好的抑制效果,因此具有优异的预防、治疗或改善增生性瘢痕或瘢痕瘤的效果。
根据一个示例性实施方案,“ZAG蛋白衍生的肽”可以是表2所示的ZAG蛋白衍生的肽Z15聚体_1、Z15聚体_2、Z15聚体_3和Z15聚体_4之一(分别为SEQ ID NOS:19至22)。
Z1至Z18肽或Z15聚体_1、Z15聚体_2、Z15聚体_3和Z15聚体_4肽仅仅是根据本发明的“ZAG蛋白衍生肽”的实例,并且“ZAG蛋白衍生肽”可以是Z1至Z18或Z15聚体_1、Z15聚体_2、Z15聚体_3和Z15聚体_4的部分序列。或者,肽可以包括相应肽的重叠部分。
例如,根据本发明的“来自ZAG蛋白的肽”可以包括与Z1至Z18肽或Z15聚体_1、Z15聚体_2、Z15聚体_3和Z15聚体_4肽的氨基酸序列具有75%或更多、优选80%或更多、更优选90%或更多、最优选95%或更多序列同源性的氨基酸序列。
此外,“ZAG蛋白衍生的肽”可以包括细胞渗透性肽、靶向序列、标签、标记残基和为了增加肽的半衰期或稳定性的特定目的而制备的氨基酸序列,以及构成活性肽的氨基酸序列,即ZAG蛋白的片段。例如,本发明可以是融合肽,其中细胞渗透性肽、靶向序列、标签、标记残基和为了增加肽的半衰期或稳定性的特定目的而制备的氨基酸序列融合至Z1至Z18肽或Z20聚体-1、Z20聚体-2、Z20聚体-3、Z15聚体-1、Z15聚体-2、Z15聚体-3和Z15聚体-4肽之一的任何一端。
此外,根据本发明的“ZAG蛋白衍生的肽”也可以包括其功能性变体。功能性变体包括本发明中描述的“ZAG蛋白衍生的肽”的生物等同物。例如,为了进一步改善肽的结合亲和力和/或其他生物学特性,可以对肽的氨基酸或多核苷酸序列进行额外的改变。这种修饰包括抗体氨基酸序列中残基的缺失、插入和/或取代,并且是基于氨基酸侧链取代基的相对相似性,例如疏水性、亲水性或电荷大小而进行的。根据氨基酸侧链取代基的大小、形状和类型,可以看出精氨酸、赖氨酸和组氨酸都是带正电荷的残基;丙氨酸、甘氨酸和丝氨酸具有相似的大小;苯丙氨酸、色氨酸和酪氨酸具有相似的形状。因此,基于这些考虑,精氨酸、赖氨酸和组氨酸;丙氨酸、甘氨酸和丝氨酸;苯丙氨酸、色氨酸和酪氨酸;和类似物可以说是生物功能性等同物。
此外,本发明的肽可以通过本领域众所周知的各种方法获得。作为一个实例,肽可以使用多核苷酸重组和蛋白表达系统来制备,并且可以通过化学合成的体外合成方法(如肽合成、无细胞蛋白质合成方法等)来制备。
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、效力、功效等)、修饰的特异性(例如,广泛的生物活性谱)和降低的抗原性,保护基团可以结合到肽的N-或C-末端。优选地,保护基团可以包括乙酰基、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),但是可以包括能够修饰肽,特别是提高肽稳定性的任何成分,而没有限制。本发明中使用的术语“稳定性”是指储存稳定性(例如,室温储存稳定性)以及用于保护本发明的肽免受体内蛋白酶攻击的体内稳定性。
本发明的“ZAG蛋白衍生的肽”可以以基于组合物的总重量0.0001至50重量%包含在药物组合物或化妆品组合物中,但是本发明不限于此。除了ZAG蛋白衍生的肽之外,根据本发明的药物组合物或化妆品组合物可以进一步包含一种或多种表现出相同或相似功能的活性成分。
本发明的ZAG蛋白衍生的肽可以通过药学上、生理学上或美容学上可接受的载体递送到受试者体内,所述载体例如是胶体悬液、粉末、生理盐水、脂质、脂质体、微球或纳米球形颗粒。这些肽可以与递送工具形成复合物或者可以与递送工具结合,并且可以使用本领域已知的递送系统递送到体内,所述递送系统例如脂质、脂质体、微粒、聚合物、缩合试剂、多糖、聚氨基酸、树枝状聚合物(dendrimer)、皂苷、吸附增强物质或脂肪酸。
此外,药学上、生理学上或美容学上可接受的载体可包括乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、阿拉伯树胶、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、矿物油等,它们通常用于制备,但本发明不限于此。此外,除了上述组分之外,可以进一步包含润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。
已经证实,根据本发明的ZAG蛋白衍生的肽通过抑制瘢痕(优选增生性瘢痕或瘢痕瘤)中细胞的增殖和迁移而对瘢痕的形成具有抑制作用,并且在通过抑制在瘢痕中过度表达的RNA和蛋白质的表达来预防、治疗和改善瘢痕中也非常有效。
因此,本发明进一步提供了用于预防、治疗或改善瘢痕的药物或化妆品组合物,其包含ZAG蛋白衍生的肽。
在本发明中,术语“预防”是指通过施用包含根据本发明的ZAG蛋白衍生的肽的药物或化妆品组合物来抑制或延缓瘢痕(优选“增生性瘢痕”或“瘢痕瘤”)的所有作用。
在本发明中,术语“治疗”是指通过施用包含根据本发明的ZAG蛋白衍生的肽的药物或化妆品组合物来缓解或有益地改变瘢痕(优选“增生性瘢痕”或“瘢痕瘤”)的症状的所有作用。
在本发明中,术语“改善”是指通过施用包含根据本发明的ZAG蛋白衍生的肽的药物或化妆品组合物来缓解瘢痕(优选“增生性瘢痕”或“瘢痕瘤”)的症状的所有作用。
在本发明中,术语“受试者”是指需要预防、治疗和改善瘢痕(优选“增生性瘢痕”或“瘢痕瘤”)的受试者,更具体地说,是指哺乳动物,如人类或非人类灵长类动物、小鼠、狗、猫、马、牛等。
ZAG蛋白衍生的肽可以肠胃外或口服向受试者施用。因为ZAG蛋白衍生的肽可以用于预防、治疗或改善瘢痕(优选“增生性瘢痕”或“瘢痕瘤”)所以ZAG蛋白衍生的肽可以制备成药物或化妆品组合物,其可以肠胃外施用,特别是施用至皮肤上,并且局部施用,但是本发明不限于此。例如,ZAG蛋白衍生的肽可以配制成诸如软膏、凝胶、霜剂、洗液等剂型。局部施用的类型可以是,例如,施用至皮肤上、使用微针的透皮渗透、皮内注射等,但是本发明不限于此。例如,该组合物可以优选地施用至皮肤上,或者包含该组合物的贴剂制剂可以优选地附着在皮肤上。
该组合物可以进一步包括药理学或生理学上可接受的载体、赋形剂或稀释剂,以及上述用于施用的ZAG蛋白衍生的肽。可包含在组合物中的合适的载体、赋形剂和稀释剂的实例包括乳糖、葡聚糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、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、滑石粉、硬脂酸镁、矿物油等。当配制组合物时,组合物可以进一步包括常规的填充剂、填充剂、粘合剂、崩解剂、表面活性剂、抗凝剂、润滑剂、润湿剂、芳香剂、乳化剂、防腐剂等。
该组合物的制剂可以包括用于向皮肤和其它组织施用的固体、乳剂(包括微乳剂)、悬浮液、霜剂、洗剂、凝胶、粉末或其它典型固体或液体组合物,其中本发明的组合物向所述皮肤和其它组织施用。这种组合物可以额外包含抗微生物剂、保湿剂、水合剂、渗透剂、防腐剂、乳化剂、天然或合成油、溶剂、表面活性剂、洗涤剂、胶凝剂、润肤剂、抗氧化剂、芳香剂、填充剂、增稠剂、蜡、除臭剂、染料、着色剂、粉末、粘度控制剂和水,并且可以任选地包含麻醉剂、止痒活性剂、植物提取物、调理剂,深色或浅色剂、闪光剂、湿润剂、云母、矿物质、多酚、硅酮或其衍生物、防晒剂、维生素和植物药。
本发明的一个实施方案可以提供包含ZAG蛋白衍生的肽的化妆品组合物。更具体地,化妆品组合物可以是用于改善瘢痕(优选增生性瘢痕或瘢痕瘤)的化妆品组合物。化妆品组合物可以具有选自由悬浮液、乳液、凝胶和糊剂组成的组的制剂,但是本发明不限于此。
组合物的剂量根据受试者的体重、年龄、性别、健康状况和饮食、施用时间、施用方法、排泄率、疾病的严重程度等而变化。每日剂量可以是大约0.001至100mg/kg,例如0.01至10mg/kg,但是本发明不限于此。该组合物可以每天施用一次或分剂量施用。
本发明提供了一种预防、治疗或改善瘢痕(优选增生性瘢痕或瘢痕瘤)的方法,其包括:向受试者施用治疗或生理有效量的ZAG蛋白衍生的肽。
将参考以下实施方案更详细地描述本发明。然而,本领域的技术人员应该理解,以下实施方案并不旨在限制本发明的范围,并且在不脱离从所附权利要求中描述的细节得出的技术细节的情况下,各种修改、变化或应用是可能的。
[发明方式]
实施例
制备实施例1:肽的合成、分离和纯化
为了在ZAG蛋白中发现包括活性位点的肽,选择18种候选肽(Z1至Z18,每种具有SEQ ID NO:1至18),使得在整个298个氨基酸序列(GenBank:AAH05306.1)(SEQ ID NO:23)中有15个氨基酸重叠。每种肽都是通过固相肽合成方法制备的。
通过HPLC分析证实,在本发明中合成的肽具有90%或更高的纯度。通过质谱测定纯化肽的分子质量。
下表1列出了用于发现ZAG蛋白活性位点的候选肽和氨基酸序列。
[表1]
实施例1:使用CCK-8检测的肽选择
进行CCK-8检测以在18个候选肽中选择对应于ZAG核心活性区的氨基酸序列,其对瘢痕形成具有抑制作用。用浓度为10μg/mL的ZAG蛋白衍生的肽候选物(Z1至Z18)和ZAG蛋白(ZAG)处理人真皮成纤维细胞(HDF)和瘢痕瘤成纤维细胞(KF),然后使用CCK-8检测证实细胞增殖。单独用ZAG蛋白处理的组用作阳性对照,未处理的组用作阴性对照。
证实细胞增殖的结果显示在图1中。
图1是显示当用Z1至Z18肽处理时,通过CCK-8检测确认人真皮成纤维细胞(HDF)和瘢痕瘤成纤维细胞(KF)增殖的结果的图。
如图1所示,与未处理的阴性对照(Con)相比,仅用ZAG蛋白处理的阳性对照(ZAG)在HDF和KF中均显示细胞增殖降低。
特别地,可以看出,在候选肽中,Z16肽(16)在HDF和KF中都显示出最低的细胞增殖。从这些结果可以证实,Z16是对应于核心活性区域的物质,其对增生性瘢痕或瘢痕瘤的形成具有抑制作用。
实施例2-1:使用划痕检测确认对增生性瘢痕或瘢痕瘤形成的抑制
将HDF和KF接种在6孔板中。24小时后,在每个孔的中心划开一个伤口。此后,用10ng/mL的TGF-β(其在瘢痕形成过程中过表达)处理HDF检测组,以产生瘢痕环境,然后用选择的Z16肽处理。24小时后证实了受影响区域的细胞迁移。
图2是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z16处理时,对细胞迁移的抑制作用的图。
在HDF的情况下,可以看出,与未治疗组(对照组)相比,由于TGF-β处理组(TGF-β)中的细胞迁移,大多数受影响的区域充满了细胞,但在用TGF-β和Z16处理的组(TGF-β+ZAG16)中,这些细胞的迁移受到抑制(图2a)。
此外,在KF的情况下,可以看出,在Z16处理组(ZAG 16)中,受影响区域中的细胞迁移受到抑制(图2b)。基于这些结果,可以看出Z16不仅参与细胞增殖,而且参与细胞迁移,因此有效抑制增生性瘢痕和瘢痕瘤的形成。
实施例2-2:确认抑制与增生性瘢痕或瘢痕瘤形成相关的蛋白质和RNA的表达
在与实施例2-1中相同的条件下用Z16处理细胞,并分析参与增生性瘢痕或瘢痕瘤形成的RNA和蛋白质的表达。通过PCR和蛋白质印迹证实表达。
图3是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z16处理时,对RNA和蛋白表达的作用的图。这里,图3a和图3b和3c分别表示RNA的表达和蛋白质的表达。
在HDF的情况下,可以看出,与未处理的阴性对照(图3a中的对照和图3b中的HDF)相比,在TGF-β处理的组(TGF-β)中,胶原I、III和TGF-β的mRNA表达以及胶原I、III、TGF-β和pSMAD2/3的蛋白表达增加,但是在用TGF-β和Z16处理的组(TGF-β+ZAG-16)中,mRNA和蛋白表达减少。
此外,在KF的情况下,可以看出,在未处理的阴性对照(图3a中的对照和图3c中的KF)中,胶原I、III和TGF-β的mRNA表达以及胶原I、III、TGF-β和pSMAD2/3的蛋白表达(其表达水平高于HDF)在Z16处理组(KF+ZAG)中降低。基于这些结果,可以看出Z16抑制了与增生性瘢痕或瘢痕瘤形成相关的RNA和蛋白质的表达。
制备实施例2:ZAG衍生肽的额外合成
基于从18个肽候选物(Z1至Z18)中选择的作为对瘢痕(增生性瘢痕或瘢痕瘤)的形成具有抑制作用的ZAG的核心活性位点的ZAG16肽(Z16),另外合成了Z16衍生的寡肽以鉴定核心活性位点(表2)。表2中的每种肽都是通过固相肽合成方法制备的。通过HPLC分析证实,在本发明中合成的肽具有90%或更高的纯度。通过质谱测定纯化肽的分子质量。
下表2列出了用于发现ZAG蛋白活性位点的候选肽和氨基酸序列。
[表2]
实施例3:使用CCK-8检测确认ZAG衍生肽的活性位点
进行CCK-8检测以选择对应于Z16核心活性区的氨基酸序列,其对增生性瘢痕或瘢痕瘤形成具有抑制作用。
具体地,用在制备实施例2中另外合成的浓度为10μg/mL的ZAG蛋白(ZAG)、Z16和ZAG蛋白衍生的肽候选物(Z15聚体_1至Z15聚体_4)处理HDF和KF,然后通过CCK-8检测证实细胞增殖。
图4是显示当另外合成寡肽,然后用寡肽处理HDF和KF以鉴定ZAG衍生的肽的核心活性位点时,通过CCK-8检测证实细胞增殖的结果的图。
如图4所示,可以看出,在寡肽候选物中,用Z15聚体-1处理的检测组在HDF和KF试验组中都显示出最低的增殖。由此,可以确认Z15聚体-1是对应于Z16的核心活性区域的物质。基于这些结果,可以看出Z15聚体-1是对应于Z16的核心活性区域的物质。
实施例4-1:使用划痕检测确认对增生性瘢痕或瘢痕瘤形成的抑制
将HDF和KF接种在6孔板中。24小时后,在每个孔的中心划开一个伤口生成模型。此后,用10ng/mL的TGF-β(其在瘢痕形成过程中过表达)处理HDF检测组,以产生瘢痕环境,然后用在制备实施例2中额外合成的Z15聚体_1至Z15聚体_4处理。24小时后证实了受影响区域的细胞迁移。
图5是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z15聚体_1至Z15聚体_4处理时,对细胞迁移的抑制作用的图。
在HDF的情况下,可以看出,与TGF-β处理组(TGF-β)相比,当TGF-β用Z16、Z15聚体_1至Z15聚体-4处理时,受影响区域的细胞迁移受到抑制。特别地,可以看出,用TGF-β和Z15聚体_1处理的检测组(15聚体_1)显示出对受影响区域中细胞迁移的最大抑制。
此外,在KF的情况下,可以看出,用Z15聚体_1处理的检测组(15聚体_1)显示出对受影响区域中细胞迁移的最大抑制。基于这些结果,可以看出Z16的核心活性区对应的Z15聚体_1比ZAG16更有效地抑制了增生性瘢痕和瘢痕瘤的形成。
实施例4-2:确认抑制与增生性瘢痕或瘢痕瘤形成相关的蛋白质和RNA的表达
在与实施例3-1中相同的条件下用Z16处理细胞,并分析参与增生性瘢痕或瘢痕瘤形成的RNA和蛋白质的表达。通过PCR和蛋白质印迹证实表达。
图6是显示当在体外产生的瘢痕形成环境中培养的HDF或在普通培养基中培养的KF被刮擦并用Z15聚体_1至Z15聚体_4处理时对RNA和蛋白表达的作用的图。
在HDF的情况下,可以看出,与TGF-β处理组(TGF-β)相比,TGF-β和Z15聚体_1处理组(TGF-β+15聚体_1)中胶原I、III和TGF-β的mRNA表达以及胶原I、III、TGF-β和pSMAD2/3的蛋白表达降低。
此外,在KF的情况下,可以看出胶原I、III和TGF-βmRNA和胶原I、III、TGF-β和pSMAD2/3蛋白在未处理的阴性对照(图6a中的对照和图6c中的KF)中以高于HDF的水平表达,但是在Z15聚体_1处理组(KF+15聚体_1)中mRNA和蛋白表达降低。基于这些结果,可以看出Z15聚体_1以与ZAG16(Z16)一样的程度抑制了与增生性瘢痕或瘢痕瘤形成相关的RNA和蛋白质的表达。
[工业适用性]
根据本发明的ZAG蛋白衍生的肽可以通过抑制瘢痕中细胞的过度增殖和迁移而对瘢痕的形成具有抑制作用,所述瘢痕优选为由过度形成纤维引起的增生性瘢痕或瘢痕瘤。
此外,ZAG蛋白衍生的肽可以通过抑制RNA和蛋白在瘢痕中过表达而具有预防、治疗或改善瘢痕的效果,所述瘢痕优选为增生性瘢痕或瘢痕瘤。
<110> 爱恩斯生物有限公司
<120> 用于改善瘢痕和瘢痕瘤的包含ZAG衍生的肽的组合物
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<400> 10
Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln Ala Leu Gly
1 5 10 15
Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys Asp
20 25 30
<210> 11
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 11
Arg Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met Glu
1 5 10 15
Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp
20 25 30
<210> 12
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 12
Pro Phe Asp Pro Ala Ala Gln Ile Thr Lys Gln Lys Trp Glu Ala Glu
1 5 10 15
Pro Val Tyr Val Gln Arg Ala Lys Ala Tyr Leu Glu Glu Glu
20 25 30
<210> 13
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 13
Cys Pro Ala Thr Leu Arg Lys Tyr Leu Lys Tyr Ser Lys Asn Ile Leu
1 5 10 15
Asp Arg Gln Asp Pro Pro Ser Val Val Val Thr Ser His Gln
20 25 30
<210> 14
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 14
Ile Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser
1 5 10 15
Asn Gly Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile
20 25 30
<210> 15
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 15
Glu Asn Asn Arg Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly
1 5 10 15
Lys Asp Tyr Ile Glu Phe Asn Lys Glu Ile Pro Ala Trp Val
20 25 30
<210> 16
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 16
Ala Pro Gly Glu Lys Lys Lys Leu Lys Cys Leu Ala Tyr Asp Phe Tyr
1 5 10 15
Pro Gly Lys Ile Asp Val His Trp Thr Arg Ala Gly Glu Val
20 25 30
<210> 17
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 17
Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His Asn Gly Asn Gly Thr
1 5 10 15
Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro Gln Asp Thr
20 25 30
<210> 18
<211> 30
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 18
Ala Val Pro Pro Gln Asp Thr Ala Pro Tyr Ser Cys His Val Gln His
1 5 10 15
Ser Ser Leu Ala Gln Pro Leu Val Val Pro Trp Glu Ala Ser
20 25 30
<210> 19
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 19
Ala Pro Gly Glu Lys Lys Lys Leu Lys Cys Leu Ala Tyr Asp Phe
1 5 10 15
<210> 20
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 20
Lys Lys Leu Lys Cys Leu Ala Tyr Asp Phe Tyr Pro Gly Lys Ile
1 5 10 15
<210> 21
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 21
Leu Ala Tyr Asp Phe Tyr Pro Gly Lys Ile Asp Val His Trp Thr
1 5 10 15
<210> 22
<211> 15
<212> PRT
<213> 人工序列
<220>
<223> ZAG蛋白衍生的肽
<400> 22
Tyr Pro Gly Lys Ile Asp Val His Trp Thr Arg Ala Gly Glu Val
1 5 10 15
<210> 23
<211> 298
<212> PRT
<213> 智人
<400> 23
Met Val Arg Met Val Pro Val Leu Leu Ser Leu Leu Leu Leu Leu Gly
1 5 10 15
Pro Ala Val Pro Gln Glu Asn Gln Asp Gly Arg Tyr Ser Leu Thr Tyr
20 25 30
Ile Tyr Thr Gly Leu Ser Lys His Val Glu Asp Val Pro Ala Phe Gln
35 40 45
Ala Leu Gly Ser Leu Asn Asp Leu Gln Phe Phe Arg Tyr Asn Ser Lys
50 55 60
Asp Arg Lys Ser Gln Pro Met Gly Leu Trp Arg Gln Val Glu Gly Met
65 70 75 80
Glu Asp Trp Lys Gln Asp Ser Gln Leu Gln Lys Ala Arg Glu Asp Ile
85 90 95
Phe Met Glu Thr Leu Lys Asp Ile Val Glu Tyr Tyr Asn Asp Ser Asn
100 105 110
Gly Ser His Val Leu Gln Gly Arg Phe Gly Cys Glu Ile Glu Asn Asn
115 120 125
Arg Ser Ser Gly Ala Phe Trp Lys Tyr Tyr Tyr Asp Gly Lys Asp Tyr
130 135 140
Ile Glu Phe Asn Lys Glu Ile Pro Ala Trp Val Pro Phe Asp Pro Ala
145 150 155 160
Ala Gln Ile Thr Lys Gln Lys Trp Glu Ala Glu Pro Val Tyr Val Gln
165 170 175
Arg Ala Lys Ala Tyr Leu Glu Glu Glu Cys Pro Ala Thr Leu Arg Lys
180 185 190
Tyr Leu Lys Tyr Ser Lys Asn Ile Leu Asp Arg Gln Asp Pro Pro Ser
195 200 205
Val Val Val Thr Ser His Gln Ala Pro Gly Glu Lys Lys Lys Leu Lys
210 215 220
Cys Leu Ala Tyr Asp Phe Tyr Pro Gly Lys Ile Asp Val His Trp Thr
225 230 235 240
Arg Ala Gly Glu Val Gln Glu Pro Glu Leu Arg Gly Asp Val Leu His
245 250 255
Asn Gly Asn Gly Thr Tyr Gln Ser Trp Val Val Val Ala Val Pro Pro
260 265 270
Gln Asp Thr Ala Pro Tyr Ser Cys His Val Gln His Ser Ser Leu Ala
275 280 285
Gln Pro Leu Val Val Pro Trp Glu Ala Ser
290 295
Claims (10)
1.一种用于预防或治疗瘢痕的药物组合物,其包含锌-α-2-糖蛋白(ZAG)蛋白衍生的肽。
2.根据权利要求1所述的药物组合物,其中所述瘢痕包括增生性瘢痕、瘢痕瘤、萎缩性瘢痕或其组合。
3.根据权利要求1所述的药物组合物,其中所述ZAG蛋白衍生的肽是由10聚体或以上且30聚体或以下的氨基酸序列组成的肽,其包括ZAG蛋白的片段。
4.根据权利要求3所述的药物组合物,其中所述ZAG蛋白的片段由选自SEQ ID NO:1至18的任意一种氨基酸序列组成。
5.根据权利要求3所述的药物组合物,其中所述ZAG蛋白的片段由选自SEQ ID NO:19至22的任意一种氨基酸序列组成。
6.一种用于改善瘢痕的化妆品组合物,其包含ZAG蛋白衍生的肽。
7.根据权利要求6所述的化妆品组合物,其中所述瘢痕是增生性瘢痕、瘢痕瘤、萎缩性瘢痕或其组合。
8.根据权利要求6所述的化妆品组合物,其中所述ZAG蛋白衍生的肽是由10聚体或以上且30聚体或以下的氨基酸序列组成的肽,其包括ZAG蛋白的片段。
9.根据权利要求8所述的化妆品组合物,其中所述ZAG蛋白的片段由选自SEQ ID NO:1至18的任意一种氨基酸序列组成。
10.根据权利要求8所述的化妆品组合物,其中所述ZAG蛋白的片段由选自SEQ ID NO:19至22的任意一种氨基酸序列组成。
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PCT/KR2021/005559 WO2022234868A1 (ko) | 2021-05-03 | 2021-05-03 | Zag 유래 펩타이드를 포함하는 흉터 및 켈로이드 개선용 조성물 |
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CN117295512A true CN117295512A (zh) | 2023-12-26 |
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CN202180097683.5A Pending CN117295512A (zh) | 2021-05-03 | 2021-05-03 | 用于改善瘢痕和瘢痕瘤的包含zag衍生的肽的组合物 |
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CN103068400A (zh) * | 2010-06-25 | 2013-04-24 | 阿斯顿大学 | 具有脂类动员性质的糖蛋白及其治疗用途 |
US20140072613A1 (en) * | 2012-09-10 | 2014-03-13 | Cynthia Lander | Compositions and Methods for Treating Cutaneous Scarring |
KR102028245B1 (ko) * | 2016-04-06 | 2019-10-04 | 연세대학교 산학협력단 | 피부 건조증 또는 피부 장벽 개선용 조성물 및 항알러지 조성물 |
CN111201029B (zh) * | 2017-09-29 | 2023-10-24 | 爱恩斯生物有限公司 | Zag来源肽及其用途 |
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- 2021-05-03 WO PCT/KR2021/005559 patent/WO2022234868A1/ko active Application Filing
- 2021-05-03 CN CN202180097683.5A patent/CN117295512A/zh active Pending
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