CN108473536B - 用于预防或治疗炎症性疾病的肽及其用途 - Google Patents
用于预防或治疗炎症性疾病的肽及其用途 Download PDFInfo
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- CN108473536B CN108473536B CN201780002141.9A CN201780002141A CN108473536B CN 108473536 B CN108473536 B CN 108473536B CN 201780002141 A CN201780002141 A CN 201780002141A CN 108473536 B CN108473536 B CN 108473536B
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Abstract
本发明是关于能够预防或治疗炎性疾病的肽以及其相关用途的。根据本发明二聚体形态的新型肽,不仅通过消炎作用表现出了非凡的治疗效果,而且由于其组成是非常小的肽,因此可将因外部物质入侵引起的副作用降至最低,所以本发明完全可以代替现存的炎性疾病治疗药物成为特效消炎药。
Description
技术领域
本发明是关于能够预防或治疗炎症性疾病的肽及其用途的。
本发明是在韩国凡部处的支持下,根据课题KDDF201404-04完成的,上述课题的研究管理专业机构是韩国药物发展基金会,研究企业为凡部处全周期药物开发企业,研究课题名称:利用细胞因子肽SIS-1的关节炎改善先驱物质,研究日期2014.07.01-2016.06.30。
本公开专利主张针对2016年03月09日以2016年10月17日提交于韩国专利厅的韩国申请专利10-2016-0028229,以及10-2016-0134177的优先权,上述专利申请的公开事项作为参考插入于本说明书中。
背景技术
炎症为,当细胞或组织由于某种原因受到损伤时,以希望最小化其反应并将损伤的部位恢复为原状的一系列的防御目的来表现的现象,从而引起神经及血管、淋巴管、体液反应、细胞反应,最终引起头痛、浮肿、发红、发热等而诱发功能障碍。作为诱发炎症的原因有由外伤、冻伤、烧伤、放射性物质等引起的物理要因和由诸如强酸(acid)等化学物质引起的化学要因以及由抗体反应引起的免疫要因,除此以外,也会由血管及激素不均匀而发生。因外部刺激而被损伤的细胞将分泌促炎症性细胞因子(pro-inflammatory cytokine)类及趋化因子(chemokine)、白细胞介素(interleukine)、干扰素(interferon)等多种生物介质而引起血管扩张且可透性升高,从而使抗体、补体、血浆(plasma)、吞噬细胞涌向炎症部位。这种现象成为成为发红的原因。为了消除炎症而起到去除炎症源、减轻生物体反应及症状作用的药物称为抗炎症剂。到目前为止,作为抗炎症的目的来利用的物质,作为非甾类有布洛芬(ibuprofen)、吲哚美辛(indomethacin)等,作为甾体类有地塞米松(dexamethasone)等,但在安全性方面存在问题而其使用被受限。因此,在这些侧面上,需要研发出一种具有强效抗炎且副作用最小的安全性抗炎症制剂。
作为具代表性的炎症性疾患的关节炎是人类所经受的最痛苦的疾病之一,不仅是疼痛,而且在由步行障碍引起的日常生活带来大的障碍。关节炎可大体分为由细菌引起的细菌感染性关节炎以及与细菌无关的非细菌感染性关节炎,且目前已知的关节炎种类足足百余种之多。其中最常见的为退行性关节炎、类风湿性关节炎(rheumatic arthritis)、痛风性关节炎、狼疮以及痛风等。调查结果显示,在韩国,1000人中47人患有关节炎,全国共有190万余人饱受关节炎的痛苦。关节炎作为引起长期活动障碍主要原因的疾病,在美国被指出为65岁以上老人活动障碍的最大原因。在韩国,关节炎紧随中风表现为长期活动障碍的主要原因疾病是当前现状,且已知女性因关节炎而经受痛苦的概率要大于男性。
为了治疗这种关节炎,就类风湿性关节炎而言,除了膳食及营养素的供给、夹板固定等一般保守治疗外,还可以进行消炎镇痛剂、甾体类制剂、金(gold)疗法、甾体的局部注射、免疫抑制剂法等药物治疗,手术治疗及不太适当地移动关节的限度内的物理运动治疗方法等。另一方面,对于退行性关节炎,可进行适度的运动及康复治疗、消炎镇痛剂、肾上腺皮质激素剂、软骨保护剂以及向关节内投放润滑剂等药物治疗或是手术治疗法。
上述使用于治疗关节炎的药物是用来减少疼痛及浮肿且减缓疾病的发展。但是,作为治疗关节炎的副作用,有胃肠道功能障碍,长期服用时会存在发生胃溃疡及出血的忧虑。而作为胃肠道系统副作用发生率的原因有:65岁以上的高龄、溃疡、出血史、甾体或抗凝剂合并使用、吸烟或饮酒等。为了减少上述副作用,服药后应密切观察身体状态,若发生胃肠道系统副作用,必须立即中断服用并与主管医师沟通,并更换为胃肠道系统副作用小的药(选择性消炎药、COX-2抑制剂)。目前临床常用的关节炎治疗剂主要包括:作为非甾类抗炎剂的甲氨蝶呤(methotrexate;MTX)、羟化氯喹(hydroxychloroquine)、金诺芬(auranofin)等缓解疾病的抗风湿性药物(disease-modifying antirheumatic drug;DMARD)的低分子药物,以及作为TNF-α抑制剂来研发的依那西普(Etanercept;商品名:恩利(Enbrel))、英夫利昔单抗(Infliximab;商品名:类克(Remicade))、阿达木单抗(Adalimumab;修美乐(Humira))等蛋白质类药物。上述甲氨蝶呤原本是作为抗癌药物研发的药物,虽然现在也被使用为关节炎治疗剂上,但据报告:因对正常细胞的毒性,当长时间使用时,副作用严重,最终导致50%以上的患者治疗失败。
在这样的背景下,目前是需要研发减少传统抗炎症制剂,特别是最小化关节炎治疗剂的副作用,且具有有效治疗效果的新型治疗剂的现状,且正在积极开展该治疗机的研究(韩国公开专利第10-2015-0125001),但到目前为止尚未成熟。
发明的详细说明
技术问题
本发明是为了解决上述问题而提出的,从而本发明的发明人研制出二聚体形态的肽,并利用代表性炎症疾病的类风湿性关节炎小鼠模型,确认了由给药所述肽导致的优秀的抗炎症效果,并基于此完成了本发明。
对此,本发明的目的在于提供一种由序列号1表示的氨基酸组成的肽。
而且,本发明的另一个目的在于提供一种用于预防或治疗炎症性疾病的药物组合物,其包含上述肽或对所述肽进行编码的多聚核苷酸作为有效成分。
而且,本发明的又一个目的在于提供一种用于预防或改善炎症性疾病的保健食品/化妆品组合物,其包含上述肽作为有效成分。
但是,本发明要达成的技术课题并不仅限于上文所提及的课题,本领域技术人员可通过以下内容准确地理解上文中未言及的其他课题。
解决问题的方法
为了实现如上所述的本发明的目的,本发明提供一种由序列号1表示的氨基酸组成的肽。
作为本发明的一个实例,上述肽N-或C-末端可与选自由乙酰基、芴甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基(stearyl group)、硬脂酰基(myristyl group)、聚乙二醇(PEG)组成的组中的保护基结合。
并且,本发明提供了一种用于预防或治疗炎症性疾病的药物组合物,其包含上述肽或对所述肽进行编码的多聚核苷酸作为有效成分。
作为本发明的一个实例,上述炎症性疾病可选自由特应性皮炎、牛皮癣、皮肤炎、过敏症、关节炎、鼻炎、中耳炎、咽喉炎、扁桃体炎、膀胱炎、肾炎、盆腔炎、克罗恩病、溃疡性大肠炎、强直性脊椎炎、全身性发红狼疮(systemic lupus erythematodes,SLE)、哮喘、浮肿、迟发型过敏症(IV型过敏症)、移植排斥、移植物抗宿主疾病、自身免疫性脑脊髓炎、多发性硬化症、炎症性肠病、囊性纤维化症、糖尿病性视网膜病变、缺血性再灌注损伤、血管再狭窄、肾小球肾炎以及胃肠过敏症组成的组中。
作为本发明的另一实例,上述组合物可抑制炎症性细胞因子的生成。
作为本发明的又一实例,上述组合物还包括药学上允许的载体。
作为本发明的又一实例,上述组合物可与除上述肽或对所述肽进行编码的多聚核苷酸外的其它抗炎药物同时、单独或依次合并给药。
作为本发明的又一实例,上述组合物可以制剂化为用于经口给药、肌肉给药、静脉给药、腹腔内给药、皮下给药、皮内给药或局部给药。
并且,本发明提供用于预防或改善炎症性疾病的保健食品/化妆品组合物,其包含上述肽作为有效成分。
并且,本发明提供炎症性疾病的治疗方法,其中包括将上述肽给药于个体的步骤。
并且,本发明提供上述肽的炎症性疾病治疗用途。
发明的效果
根据本发明的二聚体形态的新型肽,不仅通过抗炎作用表现出优秀的治疗效果,而且由非常小的肽组成,从而可以最小化因给药外部物质引起的副作用,所以被期待为可以以代替现有的炎症性疾病的治疗剂的有效物质来使用。
附图说明
图1是概略地表示胶原诱导关节炎的小鼠模型的制作过程及给药本发明肽(RDG二聚体(RDG dimer))的时间的模式图。
图2是在胶原诱导关节炎的小鼠模型中,诱导二次免疫反应后,周期性地测定根据用肽处理的关节炎进展指数的结果(Norma:正常小鼠,Vehicle control:对照组小鼠,RDGdimer:经RDG二聚体(RDG dimer)处理过的小鼠)。
图3是肉眼确认到用本发明的肽处理的踝关节周边浮肿及发红的缓和效果的结果。
图4是在胶原诱导关节炎的小鼠模型中,诱导二次免疫反应后,周期性地测定根据用各种浓度(0.1μmole、1μmole、10μmole)的肽处理的关节炎进展指数的结果(Normal:正常小鼠,Vehicle:对照组小鼠,RDG dimer 0.1μmole:用0.1μmole的RDG二聚体(RDG dimer)处理过的小鼠,RDG dimer(RDG二聚体)1μmole:用1μmole的RDG二聚体(RDG dimer)处理过的小鼠,RDG dimer(RDG二聚体)10μmole:用10μmole的RDG二聚体(RDG dimer)处理过的小鼠,MTX:是用氨甲喋呤处理过的小鼠)。
具体实施方式
以下,详细说明本发明。
本发明提供由序列号1表示的氨基酸合成的肽。
本发明中,“肽(peptide)”是指由通过酰胺键(或肽键)连接的两个以上的氨基酸组成的聚合物,从本发明的目的性上来说,是指具有抗炎活性的肽。不顾针对肽治疗剂的多种研究,由于肽本身大小太大而暴露出如下不足:即,很难有效地进入目标组织或细胞或肽的半衰期短而在体内被消灭的不足。本发明的技术意义在于最早查明了具有有效的抗炎活性且由10个以下氨基酸组成的、二聚体形态的肽。
本发明中的肽可由序列号1表示的氨基酸组成,并且包括与上述序列号1表示的氨基酸序列分别具有75%以上,优选80%以上,更优选90%以上,最优先95%以上的序列相同性的氨基酸序列;还可包括靶向序列、标签(tag)、被标示的残基、以增加半衰期或肽稳定性为目的制备的氨基酸序列。
并且,本发明中的肽,可通过本领域中众所周知的多种方法获得。举例来说,可利用多聚核苷酸重组及蛋白质表达系统进行制备,或通过诸如肽的合成的化学合成法在试管中合成,以及通过无细胞蛋白质合成发等来制备。
并且,为了获得更好的化学稳定性、更强的药理特性(半衰期、吸收性、效价、功效等)、被改变的特异性(例如:广范的生物学活性光谱)、减少的抗原性,肽的N-或C-末端可以与保护基结合。优选地,所述保护基可以是乙酰基、芴甲氧基羰基、甲酰基、棕榈酰基、肉豆蔻基、硬脂酰基或聚乙二醇(PEG),但只要是能够改变肽的性质,特别是能够增强肽稳定性的成分,则无限制地包括所述成分。本发明中所使用的用语“稳定性”不仅意指从在生物体内蛋白质分解酶的攻击下保护本发明肽的体内稳定性,也意指储存稳定性(例如:常温储存稳定性)。
本发明中,“多聚核苷酸(polynucleotide)”是结合有核苷酸的聚合物,起传递遗传信息的作用。在本发明的目的方面,对序列号1的肽进行编码,且可以包括与对所述肽进行编码的多聚核苷酸序列分别具有75%以上,优选80%以上,更优选90%以上,最优先95%以上的序列相同性的氨基酸序列。
本发明中所使用的用语“相同性”是为了表示与野生型氨基酸序列或多聚核苷酸序列类似的程度,而这些相同性的比较可以利用本领域众所周知的比较程序来进行,且可以将两个以上的序列之间的相同性以百分比(%)来计算。
作为本发明的其他样态,本发明提供一种包含上述肽或对所述肽进行编码的多聚核苷酸为有效成分的用于预防或治疗炎症性疾病的药物组合物;一种用于治疗炎症性疾病的、由序列号1表示的氨基酸组成的肽的用途;及一种包括将治疗学上有效量的上述肽给药于个体的炎症性疾病的治疗方法。
本发明中使用的用语“预防”意指的是通过给药根据本发明的药物组合物抑制炎症性疾病或推迟发病的所有行为。
本发明中所使用的用语“治疗”意指通过给药根据本发明的药物组合物,而炎症性疾病的症状有所好转或朝有益方向变化的所有行为。
本发明中,“个体”意指需要治疗炎症性疾病的对象,更具体地,意指人类或非-人类的灵长类、小鼠(mouse)、狗、猫、马及牛等哺乳类动物。
作为根据本发明组合物的预防或治疗对象的疾病,“炎症性疾病”意指总称以炎症为主要病变的疾病,其不限于此,但优选特应性皮炎、牛皮癣、皮肤炎、过敏症、关节炎、鼻炎、中耳炎、咽喉炎、扁桃体炎、膀胱炎、肾炎、盆腔炎、克罗恩病、溃疡性大肠炎、强直性脊椎炎、全身性发红狼疮(systemic lupus erythematodes,SLE)、哮喘、浮肿、迟发型过敏症(IV型过敏症)、移植排斥、移植物抗宿主疾病、自身免疫性脑脊髓炎、多发性硬化症、炎症性肠病、囊性纤维化症、糖尿病性视网膜病变、缺血性再灌注损伤、血管再狭窄、肾小球肾炎以及胃肠过敏症,其中,关节炎是指由细菌、外伤、自身免疫疾病等多种原因在关节内诱发为炎症性变化的疾病,优选为骨关节炎、退行性关节炎、类风湿性关节炎、分离性骨软骨炎、关节韧带损伤、关节半月板损伤、关节错位、无血性坏死以及幼年特发性关节炎。最优选为类风湿性关节炎。
根据本发明的实施例,利用RDG单体(RDG monomer)制备了二聚体(dimer)形态的肽(参考实施例1),利用作为代表性炎症性疾病的类风湿性关节炎的小鼠模型,通过关节炎进行指数的减少,以及与作为传统关节炎治疗剂的氨甲喋呤比较后确认了根据抗炎活性的治疗效果,并导出表示最佳治疗效果的肽的处理浓度为(0.1-1μmole)(参考实施例2)。
本发明中所使用的用语“抗炎活性”称作抑制炎症性的反应,上述炎症为生物体组织对某些刺激的防御反应的一个,意指与组织变质、循环障碍和渗出及组织增殖的三种症状一起发病的复杂病变。本发明的肽为这种抗炎活性中的一种,可抑制炎症性细胞因子,但并不仅限于此。
另一方面,本发明的肽或对所述肽进行编码的多聚核苷酸可以被诸如胶体悬浊液、粉末、食盐水、脂质、脂质体、微球体(microspheres)或纳米球形因子等药学上允许的载体来运输。它们与运输手段形成复合体或与其有关联,且使用诸如脂质、脂质体、微小粒子、金、纳米粒子、聚合物、聚合反应体、多糖类、聚氨基酸、树状高分子、皂角苷、增进吸附物质或脂肪酸的、本领域公知的运输系统运输至生体内。
此外,药学上允许的载体在制作时可以包含通常所使用的乳糖、葡萄糖(右旋糖)、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯树胶、橡胶、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、羟苯甲酯、羟苯丙酯、滑石、硬脂酸镁及矿物油等,但并不限于此。另外,除以上成分外,还可包括润滑剂、润湿剂、甜味剂、香味剂、乳化剂、悬浮剂、保鲜剂等。
根据目的不同,本发明的药物组合物根据使用方法可以经口服用或非经口应用(例如:使用在肌肉内、静脉内、腹腔、皮下、皮内以及局部),给药量根据患者的状态、体重、疾病程度、药物剂型、给药途径及时间有所不同,但由本领域技术人员可被适当地选择。
本发明的药物组合物,根据药学上有效的量,例如,以0.1-10μmole来给药。本发明中的“药学上有效的量”为能够使用于药物治疗的合理的受益/危险比率,意指治疗疾病时所使用的充分的量,且有效用量基准可以由根据患者的疾病的种类、严重程度、药物活性、对药物的敏感度、服用时间、给药途径及排出比率、治疗时间、包括同时所使用的药物的要素及其他在医学领域众所周知的要素来决定。根据本发明的药物组合物,可作为单独治疗剂来给药,也可与其他抗炎剂合并给药,可与传统的抗炎剂同时、单独或是按顺序给药,且单一或多种一起给药。重要的是,整体考虑上述要素而无副作用地以最小的量得到最大药效,本领域技术人员可以容易地决定这一点。
具体地,本发明的药物组合物,可以根据患者的年龄、性别、状态、体重、体内活性成分的吸收度、不活性率、排泄速度、疾病种类以及合并使用的药物有所不同,根据给药途径、肥胖严重程度、性别、体重、年龄等有所增减。
并且,作为本发明的其他样态,还提供一种用于预防或改善炎症性疾病的保健食品/化妆品组合物,其包含上述肽或对所述肽进行编码的多聚核苷酸作为有效成分。
本发明中的“改善”意指与治疗状态相关的参数,例如,至少是使症状程度有所减少的所有行为。上述保健食品组合物为了预防或改善关节炎,可在该疾病的发病阶段前或发病后,与用于治疗的药剂同时或分开使用。
在本发明的保健食品中,可将有效成分直接添加至食品,或与其他食品或食品成分一起使用,且可根据通常的方法而适当地使用有效成分。可根据其使用目的(预防或改善用)而适当地决定有效成分的混合量。一般来说,在生产食品或饮料时,本发明组合物,相对于原料,优选15重量%以下、优选10重量%以下的量来添加。但是,在以健康及卫生为目的,或以调节健康为目的长时间摄取时,所述量可在上述范围以下。
本发明的健康食品组合物,除了含有上述有效成分外,还可以没有特殊限制地含有其他成分作为必须的成分。例如,可作为如同普通的饮料可以含有香料或天然碳水化合物等作为添加成分。上述天然碳水化合物的示例,包括单糖,例如葡萄糖、果糖等;双糖,例如麦芽糖、蔗糖等;以及多糖,例如糊精、环式糊精等普通的糖,以及木糖醇、山梨糖醇、赤藓醇等糖醇。作为除上述以外的甜味剂,还可以有利地使用天然甜味剂(索马汀、甜叶菊提取物(比如:甜叶菊甙、甘草酸苷等)以及合成甜味剂(糖精、阿斯巴甜等)。可根据本领域技术人员适当地选择上述天然碳水化合物的比例。
除上述以外,本发明的保健食品还可含有各种营养剂、维生素、矿物质(电解质)、合成增味剂及天然增味剂等的增味剂、染色剂及重量剂(芝士、巧克力等)、果胶酸及果胶酸盐、海藻酸及海藻酸盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、酒精以及碳酸饮料中使用的碳酸化剂等。这些成分可以单独或组合使用,这次添加剂的比例可由本领域技术人员而被适当地选择。
本发明的化妆品组合物可制作成为本领域常见的各种剂型,比如:溶液、悬浮液、乳浊液、膏、凝胶、霜、乳液、散粉、肥皂、含有表面活性剂的清洁物、油、粉状粉底、乳状粉底、蜡状粉底以及喷雾,但并不限于此。更具体地说,可以制作成温和化妆水、营养化妆水、营养霜、按摩霜、精华、眼霜、清洁霜、清洁泡沫、清洁水、面膜、喷雾或是散粉等形式。
本发明的化妆品组合物中含有的有效载体,可根据不同剂型,使用本领域常用的载体。若本发明的剂型是膏、霜、或凝胶,作为载体成分可使用动物油、植物油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅胶、皂土、硅石、滑石或是氧化锌等。
若本发明的剂型是粉末或喷雾,作为载体成分,可以使用那么乳糖、滑石、硅石、氢氧化铝、硅酸钙或是聚酰胺粉末,特别是喷雾时,可追加地包括氯氟代烃、丙烷/丁烷或二甲醚等推进剂。
若本发明的剂型是液体或乳浊液,作为载体成分可以使用溶剂、溶解剂或是乳浊剂,例如:水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇油、1,3-丁基乙二醇油、甘油酯肪族酯、聚乙二醇或脱水山梨糖醇脂肪酸酯。
若本发明的剂型是悬浊液,作为载体成分,可以利用诸如水、乙醇或是丙二醇的液态的稀释剂;乙氧基化的异硬脂醇、聚氧乙烯山梨醇酯、聚氧乙烯脱水山梨糖醇酯的悬浊液、微晶纤维素、氢氧化铝、皂土、琼脂或黄蓍胶等。
若本发明的剂型是含有表面活性剂的清洁物,作为载体成分,可以利用脂肪族醇硫酸盐、脂肪族醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉衍生物、牛磺酸甲酯、肌氨酸盐、脂肪酸酰胺硫酸盐、烷基胺甜菜碱、脂肪族醇、脂肪酸甘油酯、脂肪族二乙醇酰胺、植物油、羊毛脂衍生物或是乙氧基化的甘油脂肪酸酯等。
本发明的化妆品组合物中包含的成分,除了有效成分和载体成分外,包括化妆品中常见的成分,例如抗氧化剂、稳定剂、溶解剂、维生素、染料以及香料等常用的辅助剂。
为了有助于理解本发明,下文将展示优选实施例,但这些实施例只是为了更容易理解本发明而提供,本发明的内容并不限于下述实施例。
[实施例]
实施例1.肽的制备
本实施例中,利用RDG单体(RDG monomer)制备RDG二聚体(RDG dimer)形态的聚合物(RDGRDG(序列1))。然后,利用高效液相色谱法(SHIMADZU Prominence HPLC)纯粹地分离合成的肽,色谱柱利用的是Shiseido capcell pak C18 Column(4.6×50mm)。另外,利用质量分析仪(HP 1100series LC/MSD)来确认合成的肽的质量。
实施例2.利用胶原诱导关节炎的小鼠模型的关节炎治疗效果分析
本实施例中,意在利用下述文献中的胶原诱导类风湿性关节炎小鼠模型(Collagen-induced arthritis(CIA)mouse model),来确认RDG二聚体(RDG dimer)对于作为代表性炎症性疾病的类风湿性关节炎的治疗效果(Nat Protoc.2007;2(5):1269-75.)。
2-1、胶原诱导关节炎的小鼠模型的制作与肽的给药
小鼠胶原诱导关节炎(Collagen-induced arthritis,CIA)模型作为与人类类风湿性关节炎具有相似特征的自身免疫疾病系统的关节炎模型,以如下的方式制作。
首先,将牛Ⅱ型胶原(Bovine type II collagen,Chondrex公司,美国)与弗氏完全佐剂(Freund's complete adjuvant,Chondr ex公司,美国)按1:1的比例混合并进行乳化后,将乳化的胶原溶液50ul向6周龄DBA/1J小鼠尾根部皮内注射而诱导初次免疫。初次免疫两周后,将牛Ⅱ型胶原与弗氏不完全佐剂按1:1的比例混合并进行乳化后,将乳化的胶原溶液50ul再次向小鼠尾根部皮内注射而诱导第二次免疫(boosting)。
二次免疫后,从第二天开始,每周三次向腹腔给药本发明的肽(RDG二聚体(RDGdimer)(1μmole)),并作为对照组(Vehicle contr ol)利用用PBS处理的组。上述胶原诱导关节炎的小鼠模型的制作过程以及本发明的肽的给药时机都图示在图1中。
2-2、关节炎严重程度评价
为了观察根据用本发明的肽处理的关节炎进展的影响,通过关节炎的进展指数对随时间推移的关节炎的严重程度进行评价。请两名对具体实验条件不了解的观察者一周三次对关节炎进行程度进行评价。此时,关节炎进展指数是根据由如下表1的Rossoliniec等的关节炎进展评价标准,以各腿按0至4分进行评价而显示总分为0至16分(四个腿的总和)。之后,取两名观察者评价的结果的平均值来数字化关节炎严重程度。
【表1】
分数 | 症状 |
0分 | 无浮肿或发红 |
1分 | 观察到脚或踝关节局部有轻微浮肿或发红 |
2分 | 观察到从踝关节到跗骨有轻微浮肿或发红 |
3分 | 观察到从踝关节到跗骨有中等程度的浮肿或发红 |
4分 | 观察到从踝关节到整个腿部有浮肿或发红且关节僵直 |
结果如表2及图2中所示,对照组小鼠(Vehicle control,PBS)中确认到以在第41天关节炎进展高达15.3的程度,与此相反,用RDG二聚体(RDG dimer)处理的组,在对照组小鼠中显著增加的关节炎进展指数,明显减少至10.3。实际上,肉眼所观察到的踝关节周边浮肿及发红程度,如图3所示,可以知道,相比于对照组,用RDG二聚体(RDG dimer)处理的组中,浮肿及发红症状明显减轻。
【表2】
2-3、确认按照肽处理浓度的效果
在本实施例中,为了确认按照肽处理浓度的效果,利用与上述实施例2-2相同的方法,用关节炎进展指数来评价根据多种浓度(0.1μmole、1μmole、10μmole)的肽处理的关节炎治疗效果。
并且,甲氨蝶呤(methotrexate;MTX),作为目前临床常用的关节炎治疗剂之一,其作为免疫抑制剂显示较为优秀的抗炎及关节炎治疗效果,但是由于其具有对正常细胞的毒性、口腔溃疡、脱发、间质性肺炎、抑制骨髓功能等副作用忧虑,因此广为人知为需要充分的用药指导,且服药后也必须非常小心的药物。对此,将上述根据多种浓度的肽处理的关节炎治疗效果与用甲氨蝶呤(1mg/kg)处理的情况进行比较。
其结果,在对照组小鼠中显著增加的关节炎进展指数,如表3及图4中所示,在用RDG二聚体(RDG dimer)处理的所有浓度中显然减少。其中,用0.1μmole浓度的RDG二聚体(RDG dimer)处理的情况下其效果是显著(第36天;4.1)。并且,这种效果与用甲氨蝶呤小鼠处理的情况近似,由此可以确认优秀的关节炎治疗效果。
【表3】
实施例3.毒性评价
在本实施例中,为了确认本发明的肽的诱发毒性与否,向小鼠腹腔给药不同浓度(0.1μmole、1μmole、10μmole)的RDG二聚体(RDG dimer),然后测定各小鼠死亡与否及体重变化。另一方面,作为对照组利用非给药组(Normal)及用PBS处理的组(PBS)。
其结果,不仅在上述实施例2-3中显示优秀的治疗效果的浓度为0.11μmole的肽,而且在1μmole或10μmole的浓度下也未观察到根据用所述肽处理的小鼠的死亡,如表4中所示,在所有浓度下,相比于对照组,小鼠的体重均未表现出大的差异,因此可知本发明的肽为不诱发生物体内毒性的安全的成分。
【表4】
综合上述结果来看,本发明的肽(RDG二聚体(RDG dimer))可以有效缓解作为代表性炎症性疾病的类风湿性关节炎的炎症反应具有明显的缓和作用,从而可以知道,可用作治疗炎症性疾病的有效物质。
上文的阐述是对本发明的举例说明,具有本发明所属技术领域常识的人在不改变本发明技术思想或必要特征的情况下,可以轻松地将本发明变形为其他具体的形态。因此,应理解为,上文中所述的实施例在所有方面是示例性的,并非是限制性的。
Claims (7)
1.一种肽,其氨基酸序列如SEQ ID NO:1所示。
2.如权利要求1所述的肽,其特征在于,N-末端或C-末端结合保护基团,N-末端保护基团选自由乙酰基、芴甲氧基羰基、甲酰基、棕榈酰基或硬脂酰基,C-末端保护基团选自肉豆蔻基或聚乙二醇基团。
3.一种药物组合物在制备预防或治疗类风湿性关节炎的药物中的应用,所述药物组合物包含氨基酸序列如SEQ ID NO:1所示的肽或对所述肽进行编码的多聚核苷酸作为有效成分。
4.如权利要求3所述的应用,其特征在于,所述肽的N-末端或C-末端结合保护基团,N-末端保护基团选自由乙酰基、芴甲氧基羰基、甲酰基、棕榈酰基或硬脂酰基,C-末端保护基团选自肉豆蔻基或聚乙二醇基团。
5.如权利要求3所述的应用,其特征在于,所述组合物还包括药学上允许的载体。
6.如权利要求3所述的应用,其特征在于,所述组合物与除了氨基酸序列如SEQ ID NO:1所示的肽或对所述肽进行编码的多聚核苷酸外的其它抗炎药物同时或依次给药。
7.如权利要求3所述的应用,其特征在于,所述组合物被制剂化为用于经口给药、肌肉给药、静脉给药、腹腔内给药、皮下给药、皮内给药或局部给药。
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KR10-2016-0028229 | 2016-03-09 | ||
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KR1020160134177A KR101897122B1 (ko) | 2016-03-09 | 2016-10-17 | 염증성 질환의 예방 또는 치료용 펩타이드 및 이의 용도 |
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US20150299252A1 (en) | 2010-11-01 | 2015-10-22 | Susavion Biosciences, Inc. | Compositions and methods for modulating innate and adaptive immune systems |
CN102499980A (zh) * | 2011-12-27 | 2012-06-20 | 中国药科大学 | 多肽在制备治疗或预防类风湿性关节炎药物中的应用 |
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