CN104507962A - 抗炎性肽及包含其的组合物 - Google Patents
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Abstract
本发明涉及具有抗炎活性的肽,其中,该肽包含SEQ ID NO:1;该肽与上述序列具有超过80%的氨基酸序列同源性;或该肽为上述肽的片段。本发明还涉及包含上述肽的炎症组合物。根据本发明,包含SEQ ID NO:1序列的肽在抑制炎症及预防性手段方面皆具有优异的功效。因此,包含本发明的肽的组合物可用作抗炎药物组合物或用作化妆品组合物,从而治疗或防止多种不同类型的炎性疾病。
Description
技术领域
本发明涉及抗炎性肽及包含该抗炎性肽的组合物。
背景技术
炎症是一种生物防御,作为保护身体不受到可能由外部物理刺激、化学刺激(例如暴露在多种过敏原下)或包括细菌、真菌及病毒在内的微生物的入侵造成的对生物组织的损伤的手段。
产生前列腺素、血栓素等的环氧合酶(COX)途径或脂氧合酶(LOX)途径可用来进行炎症信号传递。一旦炎症信号被传递,身体所发生的诸多改变之一是血管扩张,以增加炎症周边的血液供给,从而集中炎症应答所需的血细胞,例如嗜中性粒细胞。然而,当异常的生物防御应答过多地发生时,可能导致炎性疾病。为了防止这种情况,目前正在开发通过抑制炎症信号传导途径中所用的酶(例如,COX-1、COX-2、5-LOX、12-LOX等)来抑制过度的炎症应答的药物。
根据应答时间,炎症可分为急性炎症(即时应答,非特异性应答,数天至数周)、慢性炎症(延迟的应答,特异性应答,数周或更久)、亚急性炎症(急性炎症与慢性炎症之间的中间阶段,特征在于单核及多形核的混合产物)。
并且,除了肽因子之外,诸如前列腺素、白三烯、脂质因子(包括血小板活化因子(PAF))、炎症因子的合成酶、自由基(例如NO(一氧化氮))、多种细胞粘着分子、免疫系统及凝血因子等因子皆可引起炎症。
一旦细胞因已知的致炎症物质(例如外部生物因子(微生物、病毒、寄生虫)、物理因子(机械刺激、热、辐射、电)及化学因子)而受损时,会释放出组胺及激肽。释出的组胺及激肽将造成血管扩张、毛细血管通透性增加及炎症处的巨噬细胞集中,并引起血液流速增加、水肿、免疫细胞及抗体的迁移、疼痛以及发热。
目前使用的炎症治疗物为合成药物(例如布洛芬)、抗组胺剂、类固醇、可的松、免疫抑制剂和免疫激动剂;但这些药物仅暂时性地缓解炎症。这些药物无法从根本上治疗炎症,且具有诸如超敏反应和免疫系统退化等副作用。
因此,为了有效缓解炎症,已进行了开发抑制上述炎症蛋白的表达的物质的研究。然而,先前开发的抗炎物质具有若干问题。已开发出了包括非类固醇类抗炎药物(NSAID)及类固醇类抗炎药物(SAID)在内的多种类型的抗炎药物;但这些药物不但时常在服用时产生副作用,而且它们无法从根本上治愈炎症。因此,目前需要在物质上及经济上皆可行的抗炎药物。就急性或慢性炎症(例如慢性类风湿性关节炎)方面的一个例子而言,非类固醇类抗炎药物不仅会抑制COX-2酶的活性,已知它们还会抑制COX-1的活性,从而引起例如胃肠道失调等副作用。
本发明人发现,源自端粒酶的肽可具有抗炎性质,由此完成了本发明。
因此,本发明的目的在于提供一种新颖的肽。
本发明的另一个目的在于提供编码该新颖的肽的多核苷酸。
本发明的另一个目的在于提供一种具有抗炎活性的肽。
本发明的另一个目的在于提供使用此肽作为活性成分的抗炎组合物。
本发明的另一个目的在于提供使用此肽作为活性成分的化妆品组合物。
本发明的另一个目的在于提供使用此肽作为活性成分的药物组合物。
发明内容
在本发明的一个实施方式中,提供了一种具有抗炎活性的肽,其中该肽包含SEQID NO:1的氨基酸序列,或其中该肽与SEQ ID NO:1的氨基酸序列具有至少80%的同源性,或者该肽为上述肽的片段。
在另一个实施方式中,上述片段由3个或更多个氨基酸组成。举例而言,所述片段可由4、5、6、7、8、9、10、11、12、13、14或15、16、17、18、19、20、21、22、23、24、25或26个氨基酸残基组成。
在另一个实施方式中,上述肽由30个或更少个氨基酸组成。
在另一个实施方式中,上述肽由SEQ ID NO:1的氨基酸序列组成。举例而言,所述肽可由29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9或8个氨基酸残基组成。
在另一个实施方式中,上述肽源自人类端粒酶。
在本发明的一个实施方式中,提供了一种编码具有抗炎活性的肽的多核苷酸,其中该肽包含SEQ ID NO:1的氨基酸序列,或该肽与SEQ ID NO:1具有至少80%的序列同一性,或该肽为上述肽的片段。
在所述多核苷酸的另一个实施方式中,上述片段由至少3个氨基酸组成。举例而言,所述片段可由4、5、6、7、8、9、10、11、12、13、14或15、16、17、18、19、20、21、22、23、24、25或26个氨基酸残基组成。
在所述多核苷酸的另一个实施方式中,上述肽由30个或更少个氨基酸组成。举例而言,上述肽可由29、28、27、26、25、24、23、22、21、20、19、18、17、16、15、14、13、12、11、10、9或8个氨基酸残基组成。
在所述多核苷酸的另一个实施方式中,上述肽由SEQ ID NO:1的氨基酸序列组成。
在所述多核苷酸的另一个实施方式中,上述肽源自人类端粒酶。
在本发明的一个实施方式中,提供了一种包含肽作为活性成分的抗炎组合物,其中,该肽包含SEQ ID NO:1的氨基酸序列,该肽的氨基酸序列与SEQ ID NO:1的同源性超过80%,或该肽为上述肽的片段。
在所述组合物的另一个实施方式中,上述肽由至少3个氨基酸组成,参照上文。
在所述组合物的另一个实施方式中,上述肽由30个或更少个氨基酸组成,参照上文。
在所述组合物的另一个实施方式中,上述肽由SEQ ID NO:1的氨基酸序列组成。
在所述组合物的另一个实施方式中,上述肽源自人类端粒酶。
在所述组合物的另一个实施方式中,上述组合物用于治疗或预防炎性疾病。
在所述组合物的另一个实施方式中,上述组合物为用于改善或防止皮肤炎症的化妆品组合物。
在所述组合物的另一个实施方式中,上述组合物为用于治疗或预防炎性疾病的药物组合物。
在所述组合物的另一个实施方式中,上述组合物为用于治疗或预防炎症的食品组合物。
在所述组合物的另一个实施方式中,上述炎性疾病的特征在于其选自由下列疾病组成的组:(1)普遍的或局部的炎性疾病(例如,过敏症;免疫复合物病;枯草热;超敏性休克;内毒素性休克;恶病质,过热;肉芽肿病;或结节病);(2)胃肠相关疾病(例如,阑尾炎;胃溃疡;十二指肠溃疡;腹膜炎;胰腺炎;溃疡性结肠炎、急性结肠炎或缺血性结肠炎;胆管炎;胆囊炎、脂肪泻、肝炎、克罗恩氏病(Crone’s disease);或惠普尔氏病(Whipple’s Disease));(3)皮肤相关疾病(例如,牛皮癣;烧伤;晒伤;皮肤炎;荨麻疹性疣或风团);(4)血管相关疾病(例如,脉管炎(angiitis);血管炎(vasculitis);心内膜炎;动脉炎;动脉硬化;血栓性静脉炎;心包炎;充血性心力衰竭;心肌炎;心肌缺血;结节性动脉周围炎;周期性狭窄(recurrent stenosis);柏格氏病(Buerger'sdisease);或风湿热);(5)呼吸道疾病(例如,哮喘;会厌炎;支气管炎;肺气肿;鼻炎;囊性纤维化;间质性肺炎;COPD(慢性阻塞性肺病);成人呼吸窘迫综合征;粉尘病;肺泡炎;细支气管炎;咽炎;肋膜炎;或鼻窦炎);(6)骨胳、关节、肌肉及结缔组织相关疾病(例如,嗜伊红性肉芽肿;关节炎;关节痛;骨髓炎;皮肌炎;筋膜炎;佩吉特氏病(Paget's disease);痛风;牙周病;类风湿性关节炎;重症肌无力;强直性脊柱炎;或滑膜炎);(7)泌尿生殖系统失调(例如,附睪炎;阴道炎;前列腺炎;或尿道炎);(8)中枢或周围神经系统相关疾病(例如,阿尔茨海默氏病;脑膜炎;脑炎;多发性硬化症;脑梗死;脑栓塞;格-巴二氏综合征(Guillain-Barre syndrome);神经炎;神经痛;脊柱损伤;麻痹;或葡萄膜炎);(9)病毒(例如,流行性感冒;呼吸道合胞病毒;HIV;乙型肝炎;丙型肝炎;或疱疹病毒)、感染性疾病(例如,登革热;或败血症)、真菌感染(例如,念珠菌病);或细菌、寄生虫及类似微生物感染(例如,弥散性菌血症;疟疾;盘尾丝虫病;或阿米巴病);(10)自身免疫病(例如,甲状腺炎;红斑狼疮;古德帕斯丘综合征(Goodpasture's syndrome);同种异体移植排斥;移植物抗宿主病;或糖尿病);及(11)癌症或肿瘤疾病(例如,霍奇金病)。
在本发明的一个实施方式中,提供了一种通过施用所述抗炎组合物来治疗或防止炎性疾病的方法。
在本发明的一个实施方式中,提供了一种用于预防或治疗炎性疾病的试剂盒,其包含:具有抗炎活性的肽或包含所述肽的组合物,其中,该肽包含SEQ ID NO:1的氨基酸序列,该肽与SEQ ID NO:1具有超过80%的氨基酸序列同源性,或该肽为上述肽的片段;以及包括该肽或组合物的施用剂量、施用途径、施用频率及适应证中的至少一种的使用说明书。
产业实用性
根据本发明,序列为SEQ ID NO:1的肽在抑制炎症及预防性手段方面皆具有优异的功效。因此,包含本发明的肽的组合物可用作抗炎药物组合物或用作化妆品组合物,进而可治疗或防止多种不同类型的炎性疾病。
参考文献
KR2012-0130996A
KR2012-0133661A
KR2011-0060940A
US2011-0150873A1
Bonaldi T等,EMBO J,(22)5551-60,2003
Yankner BA等,Science(New York,N.Y.)[1990,250(4978):279-282]
Dahlgren KN等,J.Biol.Chem.277:32046-32053,2002.
附图说明
图1为显示出用源自PBMC的单核细胞的培养物进行TNF-αELISA的结果的图。以LPS(10ng/ml)刺激单核细胞2小时,接着分别与肽FITC、FITC-TAT、PEP 1-FITC及FITC-肽反应2小时(**P<0.01,相较于阴性对照组(FITC及FITC-TAT))。
图2为显示出以NF-κB萤光素酶转染HEK293/空白及HEK293/TLR2细胞系、接着与脂蛋白(10ng/ml)和FITC及FITC-PEP-1(4μM)反应、并温育18小时后进行萤光素酶分析的结果的图。萤光素酶的结果使用海肾荧光素酶校正而获得(**P<0.01,相较于阴性对照组(未处理)且将较于脂蛋白处理样品)。
图3呈现了在未经处理、经LPS处理、经PEP 1处理、以及经LPS+PEP 1处理的THP1细胞系中的细胞因子抑制程度。
图4呈现了经0、2.5、5.0、10、20及40μM的淀粉样-β蛋白处理的神经干细胞的存活力。
图5呈现了经0、2.5、5.0、10、20及40μM的淀粉样-β蛋白处理的神经干细胞的增殖。
图6呈现了经0、1、10、50、100及200μM的PEP 1处理的神经干细胞的存活力。
图7呈现了经0、1、10、50、100及200μM的PEP 1处理的神经干细胞的增殖。
图8呈现了经1、10、50及100μM的PEP 1处理的神经干细胞的存活力;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1处理后测量细胞的存活力(对照组未用淀粉样β蛋白及端粒酶系肽处理)。
图9呈现了经1、10、50及100μM的PEP 1处理的神经干细胞的毒性;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1处理后测量细胞毒性(对照组未用淀粉样β蛋白及端粒酶系肽处理)。
图10呈现了经1、10、50及100μM的PEP 1处理的神经干细胞的增殖;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1处理后测量细胞增殖(对照组未用淀粉样β蛋白及端粒酶系肽处理)。
图11呈现了经1、10、50及100μM的PEP 1处理的神经干细胞的迁移;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1处理后测量细胞迁移(对照组未用淀粉样β蛋白及PEP-1处理)。
图12呈现了经1、10、50及100μM的PEP 1处理的神经干细胞的凋亡;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1处理后测量细胞凋亡(对照组未用淀粉样β蛋白及端粒酶系肽处理)。
图13呈现了PEP-1在受到淀粉样β蛋白损伤的神经干细胞中的ROS(活性氧)抑制效果;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1(1、10、50及100μM)处理后测量对ROS的抑制(对照组未用淀粉样β蛋白及PEP-1处理)。
图14呈现了利用(A)2D电泳及(B)抗体阵列所分析的蛋白表达水平的结果;使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,在用不同浓度的PEP-1(1、10及50μM)处理后测量蛋白表达水平(对照组未用淀粉样β蛋白及PEP-1处理)。
图15呈现了蛋白质印迹的结果,其显示了炎症相关蛋白的表达水平:使神经干细胞受到20μM的淀粉样β蛋白的损伤,随后,用不同浓度的PEP-1(1、10及50μM)处理细胞。
图16呈现了PEP 1对淀粉样β蛋白聚集的抑制效果;(A)显示出当用1μM的淀粉样β蛋白和PEP 1(0.1、1及10μM)共同处理时淀粉样β蛋白的寡聚化减少;(B)显示了用PEP-1处理已被诱导聚集的淀粉样-β蛋白的情况。
图17呈现了PI3K抑制剂LY294002对经PEP 1处理的细胞的存活力的影响。用PEP 1处理后所增加的细胞存活力在用LY294002处理后减少。
具体实施方式
由于本发明可适应各种转化形式及实际应用实例,以下是对本发明的更详细描述。然而,这不意味着对实际应用形式的限制;应理解的是,本发明的意图在于包括所有转化形式、等价形式及替代形式中的技术概念及外延。在描述本发明时,若有关现有技术的任何详细描述被认为会破坏本发明的基本原理,则将略去该描述。
已知端粒为染色体末端的遗传物质重复序列,其防止染色体受损或与其它染色体融合。端粒的长度会在每次细胞分裂时缩短,在细胞分裂一定次数后,端粒的长度会缩得非常短以使细胞停止分裂并死亡。另一方面,已知端粒的延长可延长细胞的寿命。举例而言,癌细胞分泌一种称为端粒酶的酶,其防止端粒缩短,因而导致癌细胞的增殖。本发明是基于发现具有抗炎效果的源自端粒酶的肽而完成的。
在本发明的一个实施方式中,提供了一种具有抗炎活性的肽。所述肽包含至少一个SEQ ID NO:1的氨基酸序列,所述肽与上述序列具有超过80%的同源性,或所述肽为上述肽的片段。
本发明中具有抗炎活性的肽为具有SEQ ID NO:1的氨基酸序列的肽。SEQ IDNO:1的肽为由端粒酶的[611-626]位的16个氨基酸组成的肽。
SEQ ID NO:1EARPALLTSRLRFIPK
在本发明的一个实施方式中,提供了一种编码具有抗炎活性的肽的多核苷酸。该多核苷酸编码:包含至少一个SEQ ID NO:1的氨基酸序列的肽、与上述序列具有超过80%同源性的肽、或为上述肽的片段的肽。上述多核苷酸使得能够大量制造该肽。例如,培养包括编码肽的多核苷酸的载体可容许大量制造该肽。
本文所公开的肽可包括:包含同源性超过80%、超过85%、超过90%、超过95%、超过96%、超过97%、超过98%或超过99%的氨基酸序列的肽。并且,本发明所公开的肽可包括:包含SEQ ID NO:1或其片段的肽,和具有超过1个转变的(transformed)氨基酸、超过2个转变的氨基酸、超过3个转变的氨基酸、超过4个转变的氨基酸、超过5个转变的氨基酸、超过6个转变的氨基酸或超过7个转变的氨基酸的肽。
在本说明书及权利要求书中,术语「同源性」及「序列同一性」可互换使用,以指示两条氨基酸(或核酸,如果有关的话)序列之间的序列重叠程度。
除非另有说明,本文针对肽所用的术语「序列同一性」指的是按(nref-ndif)·100/nref计算的序列同一性,其中ndif是指当比对两个序列以使得相同的氨基酸数目最大时这两个序列中不相同的残基的数目,其中nref是指这些序列中最短的那个的残基数。因此,DNA序列agtcagtc与序列aatcaatc将具有75%的序列同一性(ndif=2且nref=8)。
在一些实施方式中,通过常规方法来确定序列同一性,例如:Smith和Waterman,1981,Adv.Appl.Math.2:482;通过相似度寻找法(Pearson和Lipman,1988,Proc.Natl.Acad.Sci.USA 85:2444);使用CLUSTAL W算法(Thompson等,1994,Nucleic AcidsRes 22:467380);利用计算机执行这些算法(Wisconsin Genetics Software Package,Genetics Computer Group中的GAP、BESTFIT、FASTA及TFASTA)。也可使用BLAST算法(Altschul等,1990,Mol.Biol.215:403-10),其软件可通过美国国家生物技术信息中心(www.ncbi.nlm.nih.gov/)获得。当使用任何上述算法时,使用「视窗(Window)」长度、空位罚分等的缺省参数。
在本发明的一个实施方式中,氨基酸序列的改变属于对肽的物理和化学特性的修改。例如,可针对提高肽的热稳定性、改变底物特异性和改变最适pH来进行氨基酸转变(transformation)。
在本发明的一个实施方式中,包含SEQ ID NO:1的氨基酸序列的肽、包含与上述序列具有超过80%的同源性的氨基酸序列的肽、或上述肽的肽片段优选由30个或更少个氨基酸组成。
在本发明的一个实施方式中,包含SEQ ID NO:1的氨基酸序列的肽、包含与上述序列具有超过80%的同源性的氨基酸序列的肽、或上述肽的肽片段包含源自端粒酶(更具体而言,智人(Homo sapiens)的端粒酶)的肽。
本文的术语「氨基酸」不仅包括天然整合成肽的22种标准氨基酸,也包括D-异构物及转变的氨基酸。因此,在本发明的特定实施方式中,本文的肽包括具有D-氨基酸的肽。另一方面,肽可包括非标准氨基酸,例如那些经翻译后修饰的氨基酸。翻译后修饰的例子包括磷酸化、糖基化、酰化(包括乙酰化、肉豆蔻酰化、棕榈酰化)、烷基化、羧基化、羟基化、糖化、生物素化、泛素化、化学性质转变(例如,β-消除脱酰亚胺作用、脱酰胺作用)及结构转变(例如,二硫键形成)。此外,也包括氨基酸的改变,氨基酸发生改变归因于在以用于形成肽缀合物的交联剂进行的结合过程中的化学反应。
本文所公开的肽可以是已从天然来源鉴定并分离出的野生型肽。另一方面,当与SEQ ID NO:1的肽片段比较时,本文所公开的肽可以是包含一个或多个替换、缺失和/或插入的氨基酸的人工突变肽。野生型多肽中(不仅在人工突变肽中)的氨基酸变动包括不影响蛋白折叠和/或活化的保守性氨基酸替换。保守性替换的例子属于由以下氨基酸组成的组:碱性氨基酸(精氨酸、赖氨酸及组氨酸)、酸性氨基酸(谷氨酸及天冬氨酸)、极性氨基酸(谷氨酰胺及天冬酰胺)、疏水性氨基酸(亮氨酸、异亮氨酸、缬氨酸及甲硫氨酸)、芳香族氨基酸(苯丙氨酸、色氨酸及酪氨酸)和小型氨基酸(甘氨酸、丙氨酸、丝氨酸及苏氨酸)。通常不会改变特定活性的氨基酸替换已为本发明所属技术领域所知。最常发生的改变为Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Tyr/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu、Asp/Gly,以及相反的改变。保守性替换的其他实例示于下表1中。
表1
原始氨基酸 | 残基替换实例 | 优选的残基替换 |
Ala(A) | val;leu;ile | Val |
Arg(R) | lys;gln;asn | Lys |
Asn(N) | gln;his;asp;lys;arg | Gln |
Asp(D) | glu;asn | Glu |
Cys(C) | ser;ala | Ser |
Gln(Q) | asn;glu | Asn |
Glu(E) | asp;gln | Asp |
Gly(G) | ala | Ala |
His(H) | asn;gln;lys;arg | Arg |
Ile(I) | leu;val;met;ala;phe;正亮氨酸 | Leu |
Leu(L) | 正亮氨酸;ile;val;met;ala;phe | Ile |
Lys(K) | arg;gln;asn | Arg |
Met(M) | leu;phe;ile | Leu |
Phe(F) | leu;val;ile;ala;tyr | Tyr |
Pro(P) | ala | Ala |
Ser(S) | thr | Thr |
Thr(T) | ser | Ser |
Trp(W) | tyr;phe | Tyr |
Tyr(Y) | trp;phe;thr;ser | Phe |
Val(V) | ile;leu;met;phe;ala;正亮氨酸 | Leu |
通过选择在下列功效方面显著不同的替换来进行肽的生物性质的实质性转变:(a)在替换区域中维持多肽主干的结构(例如折叠片或螺旋三维结构)的功效;(b)维持目标区域中的分子的电荷或疏水性的功效;或(c)维持侧链体积的功效。天然残基可通过一般的侧链性质而分为以下组:
(1)疏水性:正亮氨酸、met、ala、val、leu、ile;
(2)中性亲水性:cys、ser、thr;
(3)酸性:asp、glu;
(4)碱性:asn、gln、his、lys、arg;
(5)影响链取向的残基:gly、pro;和
(6)芳香性:trp、tyr、phe。
可通过将上述类别的成员换成另一类别来进行非保守性替换。与维持肽的正确的三维结构无关的任何半胱氨酸残基通常都可以替换为丝氨酸,因而增加了分子的氧化稳定性并预防了不正确的交联。相反地,可通过将(多个)半胱氨酸键加入肽中来增进稳定性。
肽的氨基酸变异的其他类型是抗体糖基化模式的改变。此处的术语「改变」是指碳水化合物残基的缺失和/或增加肽中不存在的至少一个糖基化残基。
肽中的糖基化通常为N-连接型或O-连接型糖基化。本文的术语「N-连接型」是指碳水化合物残基接附至天冬酰胺残基的侧链上。作为三肽序列,天冬酰胺-X-丝氨酸及天冬酰胺-X-苏氨酸(其中X为除了脯氨酸之外的任何氨基酸)为碳水化合物残基经由酶作用而附接至天冬酰胺侧链的识别序列。因此,使一条这种三肽序列存在于多肽中,便产生了潜在的糖基化位置。「O-连接型糖基化」意指将糖N-乙酰半乳糖胺、半乳糖或木糖中的一种附接至羟基氨基酸上。最常见的羟基氨基酸为丝氨酸或苏氨酸,但也可使用5-羟基脯氨酸或5-羟基赖氨酸。
通过改变氨基酸序列以含有上述三肽序列来将糖基化位点方便地加入肽中(以获得N-连接型糖基化位点)。这些改变可以通过将至少一个丝氨酸或苏氨酸残基加入第一抗体序列中或通过用这些残基进行替换来完成(以获得O-连接型糖基化位点)。
在本发明的一个实施方式中,多核苷酸为核酸分子,其可为单链或双链的、天然的或人工的DNA或RNA分子。核酸分子可为相同类型的一个或多个核酸(例如,具有相同的核苷酸序列),或为不同类型的核酸。核酸分子包含一种或多种DNA、cDNA、诱骗(decoy)DNA、RNA、siRNA、miRNA shRNA、stRNA、snoRNA、snRNA PNA、反意寡聚物、质粒及其它经修饰的核酸,但不限于此。
已知HMGB1蛋白为细胞因子。其先经历乙酰化,并因外部刺激而移位至细胞质中。随后其被分泌至细胞外,因而扮演着致炎性细胞因子的角色。因为当此活性引起炎症时,HMGB1蛋白被分泌至细胞外,且炎性疾病(例如Churg strauss综合征、类风湿性关节炎和舍格伦综合征(Sjogren’s syndrome))患者将呈现出升高的HMGB1血清水平。因此,如果即使在致炎刺激物存在时细胞核仍含有大量的HMGB1,则揭示了HMGB1未被分泌至细胞外的事实,这意味着炎症受到了抑制。
在本发明的一个实施方式中,当用包含SEQ ID NO:1的氨基酸序列的肽处理细胞、用具有与上述序列的同源性超过80%的氨基酸序列的肽处理细胞、或用上述肽的片段处理细胞时,细胞核内的HMGB1量会增加。这代表上述肽具有卓越的炎症预防或抑制功效。
并且,在本发明的特定实施方式中,包含SEQ ID NO:1的氨基酸序列的肽、具有与上述序列的同源性超过80%的氨基酸序列的肽、或上述肽的片段具有以下优点:因为在细胞内的毒性低,其具有高度可行性。
在本发明中,「炎性疾病」是宽泛的适应证,其指以炎症为主因的任何疾病或由疾病造成的炎症。具体而言,炎性疾病包括:(1)普遍的或局部的炎性疾病(例如,过敏症;免疫复合物病;枯草热;超敏性休克;内毒素性休克;恶病质、过热;肉芽肿病;或结节病);(2)胃肠相关疾病(例如,阑尾炎;胃溃疡;十二指肠溃疡;腹膜炎;胰腺炎;溃疡性结肠炎、急性结肠炎或缺血性结肠炎;胆管炎;胆囊炎、脂肪泻、肝炎、克罗恩氏病;或惠普尔氏病);(3)皮肤相关疾病(例如,牛皮癣;烧伤;晒伤;皮肤炎;荨麻疹性疣或风团);(4)血管相关疾病(例如,脉管炎;血管炎;心内膜炎;动脉炎;动脉硬化;血栓性静脉炎;心包炎;充血性心力衰竭;心肌炎;心肌缺血;结节性动脉周围炎;周期性狭窄;柏格氏病;或风湿热);(5)呼吸道疾病(例如,哮喘;会厌炎;支气管炎;肺气肿;鼻炎;囊性纤维化;间质性肺炎;COPD(慢性阻塞性肺病);成人呼吸窘迫综合征;粉尘病;肺泡炎;细支气管炎;咽炎;肋膜炎;或鼻窦炎);(6)骨胳、关节、肌肉及结缔组织相关疾病(例如,嗜伊红性肉芽肿;关节炎;关节痛;骨髓炎;皮肌炎;筋膜炎;佩吉特氏病;痛风;牙周病;类风湿性关节炎;重症肌无力;强直性脊柱炎;或滑膜炎);(7)泌尿生殖系统失调(例如,附睪炎;阴道炎;前列腺炎;或尿道炎);(8)中枢或周围神经系统相关疾病(例如,阿尔茨海默氏病;脑膜炎;脑炎;多发性硬化症;脑梗死;脑栓塞;格-巴二氏综合征;神经炎;神经痛;脊柱损伤;麻痹;或葡萄膜炎);(9)病毒(例如,流行性感冒;呼吸道合胞病毒;HIV;乙型肝炎;丙型肝炎;或疱疹病毒)、感染性疾病(例如,登革热;或败血症)、真菌感染(例如,念珠菌病);或细菌、寄生虫及类似微生物感染(例如,弥散性菌血症;疟疾;盘尾丝虫病;或阿米巴病);(10)自身免疫病(例如,甲状腺炎;红斑狼疮;古德帕斯丘综合征;同种异体移植排斥;移植物抗宿主病;或糖尿病);及(11)癌症或肿瘤疾病(例如,霍奇金病),但不限于此。
数十年来,治疗这些疾病的炎性组分已成为全球制药工业的主要目标,并且已开发出多种有用的治疗剂。例子包括皮质类固醇(被设计用来模拟皮质醇的效果的多种天然的、半合成的及合成的药剂,包括泼尼松龙、甲基泼尼松龙(methylprednisolone)、地塞米松、倍他米松、氟替卡松等)、环氧合酶抑制剂(非选择性抑制剂或cox-1选择性抑制剂,例如吲哚美辛、柳氮磺胺吡啶(sulfasalzine)及阿司匹林,以及近来的cox-2选择性抑制剂,例如塞来考昔)、白三烯阻断剂(例如孟鲁司特)及抗-TNF(例如经修饰的单克隆中和抗体,包括英夫利昔单抗(RemicadeTM)和阿达木单抗(HumiraTM);TNF受体融合蛋白,例如依那西普(EnbrelTM);以及小分子TNF-α合成抑制剂,例如沙立度胺)。
在本发明的一个实施方式中,提供了一种包含肽作为活性成分的抗炎组合物。所述肽包含SEQ ID NO:1的氨基酸序列,所述肽与上述序列具有超过80%的同源性,或所述肽为上述肽的片段。
在本发明的一个实施方式中,抗炎组合物可含有0.1μg/mg至1mg/mg、特别是1μg/mg至0.5mg/mg、更特别是10μg/mg至0.1mg/mg的包含SEQ ID NO:1的氨基酸序列的肽、包含与上述序列具有超过80%的同源性的氨基酸序列的肽、或上述肽的肽片段。当含有上述范围内的肽时,该组合物的所有安全性及稳定性均可得到满足,且就成本效益而言为适当的。
在本发明的一个实施方式中,所述组合物可应用于所有动物,包括人、狗、鸡、猪、牛、羊、豚鼠及猴。
在本发明的一个实施方式中,提供了用于以活性成分治疗或预防炎性疾病的药物组合物,所述活性成分由以下肽组成:由SEQ ID NO:1的氨基酸构成的肽,包含与上述序列具有超过80%的同源性的氨基酸序列的肽,或SEQ ID NO:1的肽片段。在本发明的一个实施方式中,所述药物组合物可以通过口服、直肠、经皮、静脉内、肌肉内、腹膜内、骨髓内、硬膜外或皮下方式来施用。
口服施用的形式可以是(但不限于)片剂、丸剂、软胶囊或硬胶囊、颗粒剂、粉末、溶液或乳液。非口服施用的形式可以是(但不限于)注射剂、滴剂、洗剂、软膏、凝胶、乳膏、悬浮液、乳液、栓剂、贴片或喷雾剂。
在本发明的一个实施方式中,若有需要的话,药物组合物可含有添加剂,例如稀释剂、赋形剂、润滑剂、粘合剂、崩解剂、缓冲剂、分散剂、表面活性剂、着色剂、芳香剂或甜味剂。在本发明的一个实施方式中,药物组合物可以用本领域的常规工业方法来制造。
在本发明的一个实施方式中,药物组合物的活性成分可根据患者的年龄、性别、体重、病理及状态、施用途径或处方医师的判断而有所变化。本领域技术人员可基于这些因素来确定剂量,举例而言,每日剂量可以是(但不限于)0.1μg/kg/日至1g/kg/日,特别是1μg/kg/日至10mg/kg/日,更特别是10μg/kg/日至1mg/kg/日,更特别是50μg/kg/日至100μg/kg/日。在本发明的一个实施方式中,可以(但不限于)每日施用1至3次所述药物组合物。
在本发明的一个实施方式中,提供了一种用于改善或防止皮肤炎症的皮肤外用组合物。所述皮肤外用组合物可含有以下活性成分:包含SEQ ID NO:1的氨基酸序列的肽,包含与上述序列具有超过80%的同源性的氨基酸序列的肽,或上述肽的肽片段。
在本发明的另一个实施方式中,提供了一种用于改善或防止皮肤炎症的化妆品组合物。所述化妆品组合物可含有以下活性成分:包含SEQ ID NO:1的氨基酸序列的肽,包含与上述序列具有超过80%的同源性的氨基酸序列的肽,或上述肽的肽片段。
在本发明的一个实施方式中,可以以所有适于局部应用的形式提供外用组合物或化妆品组合物。例如,可提供溶液、通过将油相分散于水中而获得的乳液、通过将水分散于油相中而获得的乳液、悬浮液、固体、凝胶、粉末、糊剂、泡沫或气溶胶等形式。这些形式可用本领域的常规工业方法来制造。
在本发明的一个实施方式中,在无损于主要效果的程度内,化妆品组合物可包含能够理想地增加主要效果的其它成分。在本发明的一个实施方式中,化妆品组合物可额外包含:保湿剂、软化剂、表面活性剂、UV吸收剂、防腐剂、杀真菌剂、抗氧化剂、pH调节剂、有机或无机色素、芳香剂、冷却剂或止汗剂。本领域技术人员可在无损本发明的目的及效果的程度内决定上述成份的配制比例,且基于化妆品组合物的总重量的配制比例可以为0.01重量%至5重量%,特别是0.01重量%至3重量%。
在本发明的一个实施方式中,提供了一种用于预防或抑制炎症的食品组合物。所述食品组合物可含有以下活性成分:包含SEQ ID NO:1的氨基酸序列的肽、包含与上述序列具有超过80%的同源性的氨基酸序列的肽、或上述肽的肽片段。
在本发明的一个实施方式中,食品组合物的形式不限,而可以是例如颗粒、粉末、液体及固体形式。除了活性成分之外,每种形式都可以用由本领域技术人员适当选择的工业常用成分来形成,并且能够与其它成分一起增加效果。
本领域技术人员可决定上述活性成分的剂量,且每日剂量可以是例如1μg/kg/日至10mg/kg/日,更特别是10μg/kg/日至1mg/kg/日,更特别是50μg/kg/日至100μg/kg/日,但不限于这些数量,并且可依照年龄、健康状态、并发症及其它多种因素而有所变化。
在本发明的一个实施方式中,提供了用包含SEQ ID NO:1的氨基酸序列的肽、包含与上述序列具有超过80%的同源性的氨基酸序列的肽、或上述肽的肽片段来预防或治疗炎性疾病的用途。
在本发明的一个实施方式中,提供了一种通过将上述肽应用至患者来预防或治疗炎性疾病的方法。
在本发明的一个实施方式中,提供了一种用于预防或治疗炎性疾病的试剂盒。该试剂盒可以包含:具有抗炎活性的肽或包含该肽的组合物,其中,所述肽包含SEQ IDNO:1的氨基酸序列,所述肽与上述序列具有超过80%以上的同源性,或者所述肽为上述肽的片段;以及包括该肽或组合物的施用剂量、施用途径、施用频率及适应证中的至少一种的使用说明书。
本文所用的术语意在用来描述实施方式,而非限制本发明。前面没有数字的术语并非用来限制量,而是用来表示所用术语所指的事物可以超过一个。术语「包括」、「具有」、「由……构成」及「包含」应作开放性解释(即,「包括但不限于」)。
提及数值范围是用来代替陈述该范围内的单独的数字,因此,除非明确指明,每个数字都可被解读为其中集合的单独的数字。所有范围的端值都包括在该范围内,且可以独立地组合。
除非在上下文中有另外注明或明显矛盾,否则本文所述的所有方法都可以以合适的顺序进行。除非包括在权利要求中,否则任一个实施方式及所有实施方式或示例性语言(如使用「例如」的语言)的使用是为了更清楚地描述本发明,而非限制本发明的范围。本文中,权利要求书以外的任何语言都不应被解读为本发明的必需要素。除非另有定义,本文所用的科技术语具有本发明所属领域的技术人员所通常理解的意义。
本发明的优选实施方式是本发明人已知的用于实施本发明的最佳模式。在阅读之前的描述后,优选实施方式的变化形式对本领域技术人员而言将是清楚的。本发明人希望本领域技术人员可充分使用这些变化形式,且本发明可以以本文所列方式以外的其它方式来实施。因此,在专利法允许下,本发明包括所附权利要求中所述的发明的关键点的等价形式及其变化形式。此外,除非上下文中另有明确陈述或矛盾,否则上述组成部分的任何组合情况中的所有可能的变化形式皆包括在本发明中。尽管通过示例性实施方式说明并示出了本发明,但本领域技术人员将充分理解,在不悖离权利要求所限定的本发明的精神及范围的情况下,在形式和细节上可以有多种变化。
已知炎症细胞会释出肿瘤坏死因子(TNF),特别是TNF-α,其造成多种细胞毒性反应、免疫反应及炎症反应。已知TNF-α涉及许多炎性疾病和自身免疫病的发生及延长,且当其被释放进入血液并全身作用时,会进一步导致严重的败血病和败血性休克。因为TNF-α是与活体的免疫系统广泛相关的因子,所以正在积极地开发TNF-α抑制剂。TNF-α以非活性形式被生物合成,并因受到蛋白酶的切割而变成活性形式;负责该活化的酶称作肿瘤坏死因子转化酶(TACE)。因此,抑制TACE的物质可治疗、改善或防止归因于TNF-α的疾病、病理状态、异常状态、困扰和不良症状等(KR2011-0060940A)。
高迁移率族蛋白1(HMGB1)以高浓度存在于胸腺、淋巴结、睪丸中,以及胎儿肝脏中,并且除了肝细胞及脑细胞外,其通常存在于细胞核内。所述HMGB1蛋白具有由A-box、B-box及C-末端组成的3个结构域。
据Tracey等,1999报道,HMGB1蛋白扮演着炎症诱导性细胞因子的角色,且所述HMGB1的炎症诱导机制是:通过外部刺激物导致HMGB1乙酰化,其随后从细胞核移动进入细胞质。此后,已知其会被分泌至细胞外,或被分泌至坏死的细胞外(Bonaldi T等,EMBO J,(22)5551-60,2003)。
通过附图、以下实施例及实验来进一步描述本发明,所述附图、实施例及实验仅为了阐明本发明的特定实施方式,且无论如何都不应被解释为限制本发明的范围。
实施例1
PEP-1的合成以及对PEP-1(SEQ ID NO:1)的抗炎活性的测量
实验1-1:合成PEP-1(SEQ ID NO:1)
合成了由16个氨基酸组成的具有如下化学结构1的肽(PEP-1),该肽源自人类端粒酶,序列为SEQ ID NO:1:
<化学结构1>
SEQ ID NO:1(PEP-1)按照现有的固相肽合成方法合成。具体而言,通过Fmoc固相肽合成(SPPS)、使用ASP48S(Peptron,Inc.,Daejeon,ROK)从C-端偶联各氨基酸,由此合成肽。使用了下述肽(其C-端的第一个氨基酸附接至树脂):
NH2-Lys(Boc)-2-氯-三苯甲基树脂
NH2-Ala-2-氯-三苯甲基树脂
NH2-Arg(Pbf)-2-氯-三苯甲基树脂
用于合成肽的所有氨基酸材料在N-端都受到Fmoc保护,且氨基酸残基受到可溶于酸中的Trt、Boc、t-Bu(叔丁酯)、Pbf(2,2,4,6,7-五甲基二氢-苯并呋喃-5-磺酰基)的保护。例如:
Fmoc-Ala-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Pro-OH、Fmoc-Leu-OH、Fmoc-Ile-OH、Fmoc-Phe-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Lys(Boc)-OH、Fmoc-Gln(Trt)-OH、Fmoc-Trp(Boc)-OH、Fmoc-Met-OH、Fmoc-Asn(Trt)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ahx-OH、Trt-巯基乙酸。
使用HBTU[六氟磷酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基铵]/HOBt[N-羟基苯并三唑]/NMM[4-甲基吗啉]作为偶联试剂。在20%的DMF中,使用哌啶移除Fmoc。为了从残基上移除保护或为了将合成的肽与树脂分离,使用切割混合剂[TFA(三氟乙酸)/TIS(三异丙基硅烷)/EDT(乙二硫醇)/H2O=92.5/2.5/2.5/2.5]。
通过使用固相支架并重复以下过程来合成肽:氨基酸从氨基酸保护开始,使对应的氨基酸单独反应,用溶剂洗涤并除去保护。在从树脂上切下合成的肽之后,用HPLC进行纯化,并用MS验证合成状况,随后冷冻干燥。
PEP 1的具体合成过程描述如下。
1)偶联
将受NH2-Lys(Boc)-2-氯-三苯甲基树脂保护的氨基酸(8当量)和偶联剂HBTU(8当量)/HOBt(8当量)/NMM(16当量)熔融并加入DMF中,随后使其在室温下反应2小时,接着用DMF、MeOH和DMF依次进行洗涤。
2)Fmoc去保护
将20%的哌啶加入DMF中并于室温下进行2次为期5分钟的反应,接着用DMF、MeOH和DMF依次进行洗涤。
3)通过重复进行反应1和2来制造肽的基本骨架。
4)切割:将切割混合剂加入完全合成的肽中,将肽与树脂分离。
5)将冷却用乙醚加入所获得的混合物中,随后用离心来沉淀出所收集的肽。
6)在用制备型HPLC纯化之后,用LC/MS检查分子量,冻干以产生粉末形式。
实施例2
PEP-1的抗炎活性测量
细胞系培养
在37℃和5%的CO2下,将来自韩国细胞库(Korea Cell Bank)的Raw 264.7巨噬细胞(KCBL,40071)维持在含有10%的胎牛血清(FBS;Gibco Laboratories)、100单位/mL的链霉素-青霉素(Gibco Laboratories)的达尔伯克改良的伊格尔培养基(DMEM;PAA,奥地利)中。以1×106个细胞/mL的密度将Raw 264.7细胞接种至96孔板中并温育过夜。
次日,用新鲜的培养基替换上述培养基,并将5μg/mL的肽(按实验实施例1的描述获得)加至细胞中。将细胞与肽温育30分钟后,加入50μL LPS(至1μg/mL的最终浓度),并将细胞再温育24小时。用1μg/mL脂多糖(LPS;Sigma,USA)处理诱导了炎症应答的实验样品,并用磷酸盐缓冲盐水(PBS;pH 7.2)处理对照样品。将来自每种条件的上清液样品收集于eppendorf管中,并执行进一步分析。
实验2-1:分析NO水平
使用Griess试剂系统(Promega,USA)测量Raw 264.7细胞(1×106个细胞/ml)中的一氧化氮(NO)水平。将50μl培养基加入96孔板,接着加入相同量的Griess试剂I(NED)溶液和Griess试剂II(对氨基苯磺酰胺溶液)。将细胞与这些试剂温育10分钟,之后,使用微孔板读取仪(Molecular Devices,USA)在30分钟内测量540nm下的光密度。使用亚硝酸钠标准曲线(0~100μM)来计算NO的浓度。
如下表2所示,以LPS刺激细胞增加了NO的表达,但在以LPS与PEP-1共同处理时,上述NO表达水平降低了。NO是在炎症期间产生的,且结果显示出PEP-1使NO水平减少至了对照的65%,这强力支持了PEP-1的抗炎效果。
表2:源自人类端粒酶的PEP 1的抗炎效果测量
实验2-2:对细胞因子抑制效果的分析
为了研究PEP-1对抑制促炎细胞因子产生的影响,以浓度为5μg/mL的PEP 1预先处理被浓度为1μg/mL的LPS激发的RAW 264.7细胞,将细胞再温育24小时。收集含有细胞培养基的上清液样品,并使用ELISA试剂盒(eBioscience,San Diego)分析细胞因子的水平。
在4℃下用100μL捕获抗体(在涂布缓冲液中稀释至制造商的操作规程所建议的浓度)涂布96孔板过夜。接着,在洗涤该板5次之后,每孔中加入200μL测定稀释液,并于室温下温育1小时以进行封闭。在用洗涤缓冲液洗涤各孔5次之后,将细胞培养物样品或每个细胞因子标准蛋白样品稀释,并在每孔中加入100μL各样品。在4℃下过夜温育含有样品的板。接着,在用洗涤缓冲液洗涤该板5次之后,加入100μL与抗生物素蛋白偶联的二抗,并在室温下温育1小时。
在与二抗温育之后,洗涤该板5次,并在室温下与100μL抗生物素蛋白-HRP(BDBioscience)温育30分钟。在洗涤该板7次之后,加入100μL TMB溶液(Pierce)并在室温下温育15分钟。在各孔中加入50μl 2N H2SO4来终止反应。使用微孔板读取仪测量450nm下的光密度。使用SPSS程序的ANOVA操作进行方差分析,从而进行统计学分析,并使用邓肯氏多变域检验法来验证分析之间的显著性。
实验2-3:IL-6分泌测量
如下表3所示,仅用LPS处理增加了细胞因子IL-6(白介素-6)的分泌。然而,用LPS与PEP-1共同处理显示出促炎细胞因子IL-6分泌水平的下降。更重要地,在用PEP-1处理后,促炎细胞因子的分泌水平下降了超过70%,这表明了PEP-1的强健的抗炎效果。
表3:PEP-1抑制细胞因子IL-6的产生
实验2-4:HMGB1、TNF-α、COX-2表达抑制
利用蛋白质印迹分析来确定蛋白表达水平。用PBS洗涤在含PEP-1培养基中生长的细胞,用0.05%的胰蛋白酶-EDTA处理,并离心收集细胞。将收集的细胞溶解在适当体积的裂解缓冲液中。通过离心使细胞内碎屑变为沉淀块,并利用SDS-聚丙烯酰胺凝胶电泳使来自各样品的等量蛋白分离。将分离的蛋白转移至硝化纤维膜(Schleicherand Schuell,Keene,NH,USA)上,接着测试对每种蛋白的抗体特异性。将膜与ECL(增强的化学发光)溶液(Amersham Life Science Corp.,Arlington Heights,IL,USA)一起温育;使其暴露于X光;并根据X光膜上显示的曝光程度来分析蛋白的表达水平。
进行蛋白质印迹分析来确定PEP-1对细胞因子蛋白表达的抑制效果。如下表4所示,以LPS刺激细胞增加了细胞因子的表达(HMGB1、TNF-α及COX)。然而,若用LPS和PEP-1同时处理细胞,上述促炎细胞因子的表达水平降低。结果显示,以PEP-1进行处理使促炎细胞因子水平下降了超过70%,这提供了有力的证据支持PEP-1的抗炎效果。
表4:PEP-1对促炎细胞因子的表达水平的抑制效果测量
实施例3
PEP-1对HepG2细胞中的TNF-α水平的抑制效果研究
实验3-1:细胞培养
使用Ficoll-PaqueTM PLUS(GE Healthcare Life Sciences,Piscataway,NJ,USA)从收集自健康受试对象的血样(50ml)中分离出PBMC(外周血单个核细胞)。随后将PBMC在含有20%的人血清的完全RPMI 1640培养基中富集,接着将其转移到涂布有人血清的100mm聚苯乙烯细胞培养板上30分钟。在37℃及5%的CO2下温育2小时后,使用冷的PBS(磷酸盐缓冲盐水)(Gibco/Life Technologies,Carlsbad,CA,USA)使单核细胞(monocyte)从细胞培养板底部脱离,并且在96孔板的各个孔中,在RPMI1640培养基(补充有青霉素-链霉素100mg/ml;人血清20%)中过夜培养1×105个细胞。
在萤光素酶分析中,使用了从国立首尔大学牙医学院获得的HEK293/空白(人类胚胎肾脏)细胞及稳定表达TLR2(toll样受体2)的HEK293/TRL细胞。在萤光素酶实验前一天,将2.5×105个细胞接种至12孔板的各孔内,并在DMEM(达尔伯克改良的伊格尔培养基)培养基(补充有杀稻瘟素10μg/ml;胎牛血清10%)(Invitrogen/LifeTechnologies,Carlsbad,CA,USA)中培养过夜。
实验3-2:细胞因子测定
为了在蛋白表达水平方面观察PEP-1对TNF-α水平的影响,进行了ELISA(酶联免疫吸附测定)。在96孔板中过夜培养1×105个源自PBMC的单核细胞。接着,以LPS(脂多醣;10ng/ml,Sigma)处理2小时,随后以PBS洗涤3次。接着以OPTI-MEM培养基(Invitrogen/Life Technologies,Carlsbad,CA,USA)处理1小时以诱导饥饿,用4μM的FITC(异硫氰酸荧光素)、FITC-TAT、PEP-1-FITC及FITC-PEP-1处理2小时,而后测量TNF-α水平。在培养后,收及细胞汤(cell soup),并使用ELISA试剂盒(R&D,Minneapolis,MN,USA)如下测量TNF-α的量:
TNF测量使用了夹心式ELISA法。将100μl TNF-α一抗加入预先涂布的96孔板的各孔中,并于4℃下过夜温育该板。次日,以0.5%的Tween20洗涤溶液洗涤该板3次,每次5分钟,随后加入100μl的各样品和标准溶液,并于室温下放置2小时。以如上方式洗涤该板后,将100μl的HRP偶联的二抗加入各孔中,并于室温下放置2小时。再次洗涤96孔板,并加入抗生物素蛋白/生物素进行吸光度测量。使用从标准溶液的吸光度计算得到的标准图形来定量确定各样品的TNF-α量。
以内毒素LPS(10ng/ml)刺激源自PBMC的单核细胞2小时,用OPTI-MEM使其饥饿1小时,接着以4μM的FITC、FITC-TAT、PEP 1-FITC及FITC-PEP 1处理2小时。温育之后,使用ELISA测量细胞培养基中的TNF-α水平。结果,在FITC及FITC-TAT的情况中,TNF-α水平因LPS而增加(分别为6.2ng/ml及6.7ng/ml),但在PEP-1-FITC及FITC-PEP-1的情况中,TNF-α水平显著下降(分别为0.17ng/ml及0.25ng/ml),且该差异具有统计学显著性(P<0.01)(图1)。
实验3-3:萤光素酶分析
为了研究PEP 1在炎症应答中的作用,发明人通过萤光素酶分析评估了NF-κB表达模式。首先,在12孔板中温育HEK293/空白及HEK293/TLR2(国立首尔大学牙医学院)24小时,以获得2.5×105个细胞/孔。在以PBS洗涤3次后,将培养基换成OPTI-MEM(Invitrogen/Life Technologies,Carlsbad,CA,USA)并温育4小时,接着在每孔中加入3μl Lipofectamine(Invitrogen/Life Technologies)、1μg NF-κB萤光素酶与10ng海肾萤光素酶(Promega,Madison,WI,USA)的混合物,并再次温育4小时。将脂蛋白pam3cys(10ng/ml,Sigma-Aldrich,St.Louis,MO,USA)置于除阴性对照之外的所有孔中,并以FITC(4μM)及FITC-PEP 1(4μM)处理18小时,之后以PBS洗涤3次。在通过将双萤光素酶报告基因测定系统(Promega)所提供的50μl被动性裂解缓冲液置于每孔中以溶解(裂解)细胞之后,通过TD-20/20照度计(Turner designs,Sunnyvale,CA,USA)确认了NF-κB的活化。通过共转染pCMV-海肾萤光素酶(Promega)确认了转染功效,且通过校准萤光素酶值来分析结果。
在将NF-κB萤光素酶转染至HEK293/空白及HEK293/TLR2细胞系后,用pam3cys(一种合成的脂蛋白)与FITC(4μM)(阴性对照)一起进行处理,并再次用pam3cys与FITC-PEP 1(4μM)一起处理并培养18小时。用双萤光素酶报告基因测定系统(Promega)所提供的被动性裂解缓冲液使细胞裂解,由此利用萤光素酶强度来测量NF-κB的表达模式,结果显示,以脂蛋白处理或以FITC-PEP-1处理或未处理的HEK293/空白细胞之间并无差异。然而,当以脂蛋白(TLR2的激动剂)处理HEK293/TLR2细胞系时,与未处理的细胞相比,NF-κB的表达有所增加(P<0.01),这确认了炎症应答的发生。此外,与未处理的细胞相比,当以FITC-PEP 1一起进行处理时,NF-κB的表达增加;与用脂蛋白和FITC一起处理的阴性对照相比,表达减少(P<0.01)(图2)。最终能够确认,当以PEP 1一起处理时降低了可由TLR 2引起的炎症应答。
实验3-4:对影响THP1细胞系中的细胞因子水平的肽的再次分析
使用人类急性单核细胞性白血病细胞系THP-1单核细胞系(美国典型培养物保藏中心(Manassas,VA,USA))来确认PEP 1的效果。使密度为0.5至7×105个细胞/mL的细胞在RPMI 1640(含有10%的FBS、0.05mM的2-巯基乙醇、100U/ml的青霉素及100μg/mL的链霉素)中生长,并在5%的CO2下维持于37℃。在37℃下,以100ng/mL的乙酸肉豆蔻酸佛波醇酯(PMA)处理THP-1细胞24小时,从而使THP-1细胞分化成巨噬细胞。
所有试剂及培养基皆购自Gibco BRL。PMA、LPS及2-巯基乙醇购自Sigma(St.Louis,MO,USA)。肽RIA由Peptron(Daejeon,Republic of Korea)合成。逆转录PCR试剂盒购自Promega(Madison,WI,USA)。RT2 Green qPCR Mastermix试剂及QIAzol购自QIAGEN(Valencia,CA,USA)。
分化成巨噬细胞后,使用完全RPMI 1640洗涤THP-1细胞2次(每次5分钟)。接着,在无FBS的RPMI 1640中,用10ng/ml的LPS和/或4μM的肽RIA处理细胞4小时。
使用Trizol(QIAzol)试剂从经肽处理的THP-1细胞中分离出总RNA样品,并依照制造商的操作规程,使用来自Promega的逆转录PCR试剂盒进行逆转录PCR,从而合成cDNA。
接着,使用SYBR Green系统和CFX96(Bio-Rad)仪进行实时qPCR。本实验中所用的引物列于表5中。PCR循环条件为:95℃下10分钟,以活化HotStart DNA Taq聚合酶;接着进行45个循环的95℃/10秒、55℃/30秒和72℃/30秒。对所有样品进行三次等分测量,并使用2循环阈值法计算基因表达的差异。将所有数据针对β肌动蛋白(管家基因)进行归一化,并呈现为来自至少三次独立实验的平均值+/-S.E.。
表5:用于qRT-PCR分析的引物
如图3所示,通过用PEP 1进行处理,参与炎症应答的细胞因子显著减少。
实施例4
对由淀粉样-β蛋白诱导的炎症应答的分析
HMGB1先经历乙酰化,并因外部刺激而移位至细胞质中。随后其被分泌至细胞外,因而扮演着致炎性细胞因子的角色。因为当此活性引起炎症时,HMGB1蛋白被分泌至细胞外,且炎性疾病(例如Churg strauss综合征、类风湿性关节炎和舍格伦综合征)患者将呈现出升高的HMGB1血清水平。因此,如果即使在致炎刺激物存在时细胞核仍含有大量的HMGB1,则揭示了HMGB1未被分泌至细胞外的事实,这意味着炎症受到了抑制。
实验4-1:对由PEP-1的抗炎效果导致的神经干细胞存活及增殖的分析
首先,根据实施例1中描述的制造方法来制备PEP-1。
实验4-2:神经干细胞的培养及淀粉样-β毒性评估
从孕期13天的胚胎大鼠的头部移出皮质,之后将其与碱性成纤维细胞生长因子(bFGF)培养一周,以获得神经干细胞。为了分析淀粉样β蛋白对神经干细胞的影响,以浓度为0至40μM的预先寡聚化的淀粉样β蛋白处理神经干细胞48小时,接着使用CCK-8测定、BrdU及TUNEL测定来进行细胞毒性评估(参考BA Yankner等,1990及KN Dahlgren等,2002)。在发明人确认了在以20μM的淀粉样β蛋白处理时细胞存活率降至60%(参见图4及图5)之后,在后续实验中使用相同浓度的淀粉样β蛋白。
实验4-3:以PEP-1处理时的细胞毒性评估
为了评估PEP-1对培养的神经干细胞的影响,首先用熟知的方法(BA Yankner等,1990及KN Dahlgren等,2002)培养神经干细胞。接着,以不同浓度(0、1、10、50、100、200μM)的PEP-1处理48小时,接下来使用MTT测定、BrdU及TUNEL测定来评估细胞存活力及细胞增殖。0至200μM的PEP-1浓度在神经元系统中显得稳定,因为这些浓度没有抑制神经干细胞的生存及增殖(参见图6及图7)。
实验4-4:以淀粉样β蛋白和端粒酶肽共同处理时的细胞毒性评估
为了确定PEP 1是否有抑制由淀粉样β蛋白引起的神经毒性的效果,以20μM的淀粉样β蛋白和多种浓度的PEP-1共同处理48小时。使用MMT测定、CCK-8测定、LDH测定及TUNEL测定来测量细胞存活力及细胞凋亡,并用BrdU测定来测量神经干细胞增殖。
MMT测定及CCK-8测定的结果确认了10μM的PEP-1开始保护神经干细胞免受由淀粉样β引起的神经毒性的影响,且100μM提供了最有效的保护(参见图8)。进行了LDH测定作为评估细胞死亡程度的另一种方法,且确认了由淀粉样-β导致的细胞死亡增加程度被PEP-1减少,且从1μM浓度开始即看到了功效(参见图9)。
发明人还用BrdU测定确认了当以PEP-1处理时,因淀粉样β蛋白而减少的细胞增殖得到了恢复(参见图10)。
由于神经干细胞的本质,细胞运动性是一种至关重要的因素。根据细胞运动性的实验结果,发明人确认,与对照相比,当以PEP-1处理时,因淀粉样β蛋白而减少的细胞增殖得到了恢复,且在浓度为10μM时细胞运动性增加得更多。这表示在未来的临床试验中,在干细胞移植前进行处理可以带来更有效的结果(参见图11)。
为了确认神经干细胞损伤的程度,进行了TUNEL测定。在20μM淀粉样β蛋白处理组中,观察到了神经干细胞死亡显著增加;而当以1μM至100μM的PEP 1处理时,神经干细胞死亡减少(参见图12)。
研究了PEP-1对淀粉样β蛋白引起的细胞凋亡起到保护效果的作用机制。首先,研究了PEP-1是否能将淀粉样β蛋白所造成的氧化性损伤降到最小。使用DCF-DA染色(Molecular Probes,Eugene,OR)观察用淀粉样β蛋白和PEP-1处理后的活性氧的产生上的变化。在活性氧因20μM淀粉样β蛋白而增加的组中,PEP-1(1μM、10μM、50μM)处理使增加的活性氧减少(参见图13)。
实验4-5:对以PEP-1处理的组与未以PEP-1处理的组之间的蛋白表达水平的比
较性分析
通过2D电泳技术及抗体微阵列技术分析了经PEP-1处理的组与未经PEP-1处理的组的蛋白表达水平。从实施例3的实验3-1中培养的神经干细胞中提取制备了200μg蛋白质组。此外,使用未经PEP-1处理的组作为相同条件下的比较组。
使用12%的丙烯酰胺凝胶进行2D电泳。首先使用8.5×7cm的凝胶尺寸在Pl 4~10N下进行凝胶电泳。电泳之后,用胶体考马斯蓝染色,随后使用PDQuest软件分析每个点,由此比较表达水平。
使用MALDI-TOF MS(基质辅助激光解吸电离飞行时间质谱)鉴定了超过1.5倍的表达水平差异。其中,鉴定了与炎症相关信号传导有关联的蛋白,例如i-NOS及HMGB-1(参见表6)。蛋白表达水平的变化因淀粉样β蛋白而增加或减少了1.5倍,但还确认,当加入PEP-1时,表达水平被调控至接近阴性对照的水平(参见图14)。
使用细胞信号传导试剂盒(CSAA1,PanoramaTM Ab Microarray Cell Signaling kit)来进行抗体微阵列,用GenePix Personal 4100A扫描仪(Molecular Devices)扫描阵列载片,并用GenePix Pro 5.0(Molecular Devices)分析数据。
下表6为通过2D电泳技术完成的对炎症相关蛋白的表达水平的分析。对照组呈现的是未经淀粉样β蛋白处理也未经PEP-1处理的细胞的蛋白表达水平。表6显示了基于对照组表达水平的蛋白表达水平增加或减少的倍数。
根据分析结果,发明人确认,如下表6所示,炎症相关蛋白的过表达或表达不足受到了PEP-1的控制;蛋白表达水平接近阴性对照组的水平。
表6
磷脂酰肌醇3-激酶(PI3K)/AKT信号传导途径在神经干细胞的生长及存活中扮演重要角色。PI3K途径被生长因子和调控因子活化,并参与对神经干细胞生长和存活的正常调控。AKT信号传导途径使多种促凋亡因子失效,包括熟知的凋亡信号传导分子GSK3β。
为了进一步研究PEP-1的抗炎效果,发明人对HMGB1进行了蛋白质印迹,这是因为HMGB1在蛋白质分析中显示出了较大变化。结果,PEP-1的处理增加了诸如Ki67、pAKT、PI3K、HSTF-1及Bcl-2等抗凋亡蛋白的蛋白表达水平,并降低了诸如Bax、GSK3β、细胞色素c及半胱天冬酶-3等凋亡信号的蛋白表达水平(参见图15)。
HMGB1,一种与DNA结合的非组蛋白结构蛋白,在细胞内扮演多种角色;例如稳定核小体结构及调控基因表达。作为在炎症应答后期分泌的致炎物质之一,其在炎症被刺激时由巨噬细胞和单核细胞分泌,但当神经元显著受损并导致细胞坏死时,HMGB1会被分泌至细胞外,导致剧烈的炎症应答。在神经细胞的细胞质中,在HMGB1因淀粉样β处理而减少后,PEP-1处理使HMGB1增加,这反映了PEP-1抑制HMGB1因神经元细胞死亡而被分泌至细胞外的事实;因而表示PEP-1具有强的抗炎效果(参见图15)。
此外,发明人研究了PEP-1对淀粉样β聚集的反应。在诱导淀粉样β聚集时,当以PEP-1处理时,抑制了蛋白聚集(参见图16(A)),而当用PEP-1处理已被诱导聚集的淀粉样β蛋白时,使蛋白发生了解聚(参见图16(B))。
在PEP-1作用的机制中,发明人之前已确认了PI3K的细胞存活信号传导的增加以及PI3K的凋亡信号传导的减少。为了研究这些效果是直接还是间接的,发明人用PI3K抑制剂LY294002(Promega)进行了处理。结果,当以LY294002处理时,在PEP1处理后所增加的细胞存活力有所下降。因此,发明人能够得出如下结论:PI3K与PEP 1的神经保护效果直接相关(参见图17)。
PEP-1抑制淀粉样β蛋白所导致的神经干细胞凋亡。并且,还确认了神经干细胞的细胞运动性的提高,由此表明了临床应用的多种可能性。对由β-淀粉样蛋白引起的神经毒性的抑制效果通过以下现象而得到证实:PEP 1作用机制的抗炎效果、神经干细胞的存活因子的增加以及凋亡因子的减少、特别是PI3K信号传导途径及抗氧化效过的活化。
实施例5
qPCR阵列
材料和方法
THP-1细胞培养
THP-1细胞(人单核细胞性白血病衍生细胞系)购自ATCC(美国典型培养物保藏中心,Manassas,VA,USA),并在补充有10%FBS(Life technologies)、1%青霉素-链霉素(Life technologies)和0.05mM 2-巯基乙醇(Simga-Aldrich,St.Louis,MO,USA)的PRMI-1640(Life technologies,Carlsbad,CA,USA)培养基中于37℃和5%CO2下培养。使通常以悬浮态生长的THP-1细胞在分化培养基(包含100ng/ml 12-肉豆蔻酸-13-乙酸佛波醇酯(PMA,Sigma-Aldrich)的完全生长培养基)中分化24小时成为粘附性巨噬细胞样表型。为了进行分化,将THP-1细胞(3×106个细胞/板,约95%融合)接种到10cm组织培养板中,并在分化培养基中温育。
用抗炎性肽PEP-1处理THP-1细胞
分化后,使用完全生长培养基洗涤巨噬细胞样THP-1细胞2次。随后,用10ng/ml脂多糖(Sigma-Aldrich)和/或4μM PEP-1在37℃下处理细胞4小时。
从THP-1细胞中分离RNA并合成cDNA
使用RNeasy mini试剂盒(Qiagen,Valencia,CA,USA)按照制造商的操作规程提取并纯化总RNA。使用来自Promega(Madison,WI,USA)的逆转录系统按照制造商的操作规程进行逆转录,由此合成cDNA。
PCR阵列
随后,使用来自THP-1细胞的cDNA样品作为实时定量PCR(qPCR)分析的模板。对于qPCR分析,RT2Profiler PCR阵列试剂盒购自SABiosciences/Qiagen(Valencia,CA,USA)。实验中用来分析单独的信号传导途径的四种不同的PCR阵列试剂盒如下:人信号转导途径检测物,人炎症细胞因子与受体,人转录因子,人NF-κB信号传导途径。使用SYBR Green检测系统(Qiagen)和CFX 96实时PCR仪(Bio-Rad,Mercules,CA,USA)进行PCR。热循环条件为:95℃下10秒钟;55℃下30秒种;95℃下10分钟;50个扩增循环的95℃/10秒、55℃/30秒和72℃/30秒。数据呈现了来自三次独立实验的平均值,并利用经LPS处理的样品相对于经LPS+PEP-1处理的样品的靶基因表达来确定%减少。在所分析的336个基因中,仅将显示出具有统计学显著性(p<0.05,学生T检验)的%减少的那些基因示于表7中。
结果
表7.PEP-1抑制了下表中所示的基因(*,在启动子区中含有共有的NF-κB结合位点的NF-κB靶基因)。
PEP-1抑制了表7所示的基因的转录,其中%抑制以经LPS处理的样品与经LPS+PEP-1处理的样品(THP-1细胞)之间的转录水平之比来计算。在所分析的336个基因中,仅有表7中的13个基因在PEP-1处理后显示出了具有统计学显著性的减少。这些基因可分为不同的功能类别,包括:趋化因子与细胞因子,TNFα受体信号传导,脂代谢,凋亡,和NF-κB信号传导。更重要的是,趋化因子与细胞因子类别中的基因已知为NF-κB靶基因,在它们的启动子区中含有NF-κB共有DNA结合位点。综上,来自PCR阵列的数据证明了PEP-1可以通过调节炎症NF-κB的主调控因子来发挥抗炎效果,并凭借此机制,PEP-1能够用作多种炎性疾病的抗炎治疗剂。
Claims (16)
1.一种具有抗炎活性的肽,其中,所述肽包含:
(a)SEQ ID NO:1的氨基酸序列,或
(b)与SEQ ID NO:1具有至少80%的序列同一性的氨基酸序列,或
(c)(a)或(b)的氨基酸序列的片段。
2.如权利要求1所述的肽,其中,所述片段由至少3个氨基酸组成。
3.如权利要求1所述的肽,所述肽由至多30个氨基酸组成。
4.如权利要求1所述的肽,所述肽由SEQ ID NO:1的氨基酸序列组成。
5.如权利要求1所述的肽,所述肽源自人类端粒酶。
6.一种多核苷酸,所述多核苷酸编码前述权利要求中任一项所述的肽。
7.一种抗炎组合物,所述抗炎组合物包含作为活性成分的权利要求1至5中任一项所述的肽。
8.如权利要求7所述的抗炎组合物,用于治疗或预防炎性疾病。
9.如权利要求7所述的抗炎组合物,所述抗炎组合物为用于改善或防止皮肤炎症的化妆品组合物。
10.如权利要求7所述的抗炎组合物,所述抗炎组合物为用于治疗或预防炎性疾病的药物组合物。
11.如权利要求7所述的抗炎组合物,所述抗炎组合物为用于治疗或预防炎症的食品组合物。
12.如权利要求8或10所述的抗炎组合物,其中,所述炎性疾病选自由以下疾病组成的组:(1)普遍的或局部的炎性疾病(例如,过敏症;免疫复合物病;枯草热;超敏性休克;内毒素性休克;恶病质,过热;肉芽肿病;或结节病);(2)胃肠相关疾病(例如,阑尾炎;胃溃疡;十二指肠溃疡;腹膜炎;胰腺炎;溃疡性结肠炎、急性结肠炎或缺血性结肠炎;胆管炎;胆囊炎、脂肪泻、肝炎、克罗恩氏病;或惠普尔氏病);(3)皮肤相关疾病(例如,牛皮癣;烧伤;晒伤;皮肤炎;荨麻疹性疣或风团);(4)血管相关疾病(例如,脉管炎;血管炎;心内膜炎;动脉炎;动脉硬化;血栓性静脉炎;心包炎;充血性心力衰竭;心肌炎;心肌缺血;结节性动脉周围炎;周期性狭窄;柏格氏病;或风湿热);(5)呼吸道疾病(例如,哮喘;会厌炎;支气管炎;肺气肿;鼻炎;囊性纤维化;间质性肺炎;COPD(慢性阻塞性肺病);成人呼吸窘迫综合征;粉尘病;肺泡炎;细支气管炎;咽炎;肋膜炎;或鼻窦炎);(6)骨胳、关节、肌肉及结缔组织相关疾病(例如,嗜伊红性肉芽肿;关节炎;关节痛;骨髓炎;皮肌炎;筋膜炎;佩吉特氏病;痛风;牙周病;类风湿性关节炎;重症肌无力;强直性脊柱炎;或滑膜炎);(7)泌尿生殖系统失调(例如,附睪炎;阴道炎;前列腺炎;或尿道炎);(8)中枢或周围神经系统相关疾病(例如,阿尔茨海默氏病;脑膜炎;脑炎;多发性硬化症;脑梗死;脑栓塞;格-巴二氏综合征;神经炎;神经痛;脊柱损伤;麻痹;或葡萄膜炎);(9)病毒(例如,流行性感冒;呼吸道合胞病毒;HIV;乙型肝炎;丙型肝炎;或疱疹病毒)、感染性疾病(例如,登革热;或败血症)、真菌感染(例如,念珠菌病);或细菌、寄生虫及类似微生物感染(例如,弥散性菌血症;疟疾;盘尾丝虫病;或阿米巴病);(10)自身免疫病(例如,甲状腺炎;红斑狼疮;古德帕斯丘综合征;同种异体移植排斥;移植物抗宿主病;或糖尿病);及(11)癌症或肿瘤疾病(例如,霍奇金病)。
13.一种通过施用权利要求7至12中任一项所述的抗炎组合物来治疗或防止炎性疾病的方法。
14.一种用于预防或治疗炎性疾病的试剂盒,所述试剂盒包含:权利要求1至5中任一项所述的肽;以及包括所述肽或所述组合物的施用剂量、施用途径、施用频率和适应证中的至少一种的使用说明书。
15.如权利要求1至5中任一项所述的肽,用作药物。
16.如权利要求1至5中任一项所述的肽,用于权利要求13所述的方法中。
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