CN115315433A - Tlr2交互作用的胜肽以及包括其的组合物 - Google Patents
Tlr2交互作用的胜肽以及包括其的组合物 Download PDFInfo
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- CN115315433A CN115315433A CN202180008832.6A CN202180008832A CN115315433A CN 115315433 A CN115315433 A CN 115315433A CN 202180008832 A CN202180008832 A CN 202180008832A CN 115315433 A CN115315433 A CN 115315433A
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Abstract
本发明揭示Amuc_1100*的胜肽片段及其用途。该胜肽显示为活化TLR2的配体,可用于治疗肥胖症及相关疾病或病症。本发明的胜肽进一步用于治疗小肠癌、促进免疫反应,以及肠上皮屏障功能障碍。
Description
交叉引用
本申请依据35 U.S.C.§119(a)主张2020年1月10日提交的第62/959,519号美国专利临时申请的优先权,所述申请的全部内容通过引用并入本文。
技术领域
本发明涉及一种与类铎受体2(Toll-like receptor 2,TLR2)交互作用的胜肽,以及一些用于治疗肥胖症的胜肽、其组合物及用途。
背景技术
肠道微生物组包含约100兆个微生物,与宿主的健康状况相关。据报导,肠道微生物组影响并调节宿主的代谢、营养,以及免疫反应。因此,肠道中的微生物为诊断、预防、治疗,以及预后的潜在目标。
艾克曼菌(Akkermansia spp.)为从人体肠道菌群中分离出来的细菌家族。先前已报导肥胖者及发炎性肠道疾病患者的粪便样本中的嗜黏液艾克曼菌(Akkermansiamuciniphila)数量减少。特别是,Amuc_1100蛋白,一种从嗜黏液艾克曼菌外膜分离的特定蛋白,被认为是治疗肥胖症的活性剂,因此是一种潜在的药物。当Amuc_1100与类铎受体2交互作用时,其改善肠道屏障且部分概括了该菌的有益作用。
然而,据报导,嗜黏液艾克曼菌的药物活性蛋白在用于巴斯德灭菌的温度下是稳定的,但在高压灭菌后将无效。期望找到或开发可被高压灭菌但仍保留活性的新胜肽。
发明内容
因此,本发明提供一些与类铎受体2(TLR2)交互作用的新胜肽。
本文提供的一方面为与TLR2交互作用的一合成胜肽,包含一由SEQ ID NO:8所组成的胺基酸序列;但长度最多为50个胺基酸。
于一具体实施例中,该合成胜肽具有至多30个胺基酸的长度。
于一具体实施例中,该合成胜肽由SEQ ID NO:8的胺基酸序列组成。
本文提供的另一方面为一种用于治疗TLR2相关疾病的组合物,包含一医药上可接受的载剂,以及至少一包含如SEQ ID NO:8所述的一片段的胜肽。
本文提供的另一方面为一种TLR2相关疾病的治疗方法,包含对一有需要的个体施用一治疗有效量的一合成胜肽,该合成胜肽包含一由SEQ ID NO:8组成的胺基酸序列。
于一具体实施例中,该合成胜肽经口服或肠胃外施用。
本文提供的另一方面为一种具有治疗肥胖症功效的合成胜肽,包含一选自由SEQID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组的胺基酸序列,但长度最多为50个胺基酸。
于一具体实施例中,该合成胜肽具有至多30个胺基酸的长度。
于一具体实施例中,该合成胜肽由SEQ ID NO:10的胺基酸序列组成。
于一具体实施例中,该合成胜肽由SEQ ID NO:8的胺基酸序列组成。
于一具体实施例中,该合成胜肽由SEQ ID NO:15的胺基酸序列组成。
于一具体实施例中,该合成胜肽由SEQ ID NO:19的胺基酸序列组成。
于一具体实施例中,该合成胜肽由SEQ ID NO:20的胺基酸序列组成。
本文提供的另一方面为一种用于治疗肥胖症的医药组合物,包含一医药上可接受的载剂,以及至少一种胜肽,该胜肽包含选自由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组的一片段。
本文提供的另一方面为一种治疗肥胖症的方法,包含对一有需要的个体施用一治疗有效量的一合成胜肽,该合成胜肽包含由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的一胺基酸序列。
于一具体实施例中,该合成胜肽经口服或肠胃外施用。
于一具体实施例中,该合成胜肽提供促进免疫反应的功效。
于一具体实施例中,该胜肽与一疫苗共同施用并作为一佐剂。
本文提供的另一方面为一种预防小肠癌并减少小肠致癌物毒性的方法,包含对一有需要的个体施用一治疗有效量的一分离的胜肽,该分离的胜肽包含如本文所揭示的胜肽。
于一具体实施例中,该合成胜肽经口服或肠胃外施用。
本文提供的另一方面为一种治疗一由肠上皮屏障功能障碍引起的疾病的方法,包含对一有需要的个体施用一治疗有效量的如本文所揭示的胜肽。
于一具体实施例中,该由肠上皮屏障功能障碍引起的疾病为发炎性肠道疾病、乳麋泻、腹泻病、第II型糖尿病、肥胖症,或非酒精性脂肪肝病(non-alcoholic fatty liverdisease,NAFLD)。
附图说明
当结合附图阅读时,将更好理解前述发明内容以及以下对本发明的详细描述。为了说明本发明,于附图中显示目前较佳的具体实施例。
于附图中:
图1所示为以如本文所揭示的胜肽在重组HEK-293中诱导TLR2:(A)功能上过表现人类TLR以及一报导基因(SEAP)的重组HEK-293;(B)HEK-293空白为阴性对照。仅AMS5显示出诱导TLR的活性,而其他胜肽则无。PC:阳性对照;NC:阴性对照;GST:麸胺基硫S-转移酶(空白)。
图2所示为通过如本文实施例3中揭示的胜肽处理减少斑马鱼的体重。于第0、1、3、6、9、12,以及13天测量斑马鱼的体重。
图3所示为于实施例3的第13天,以本文揭示的胜肽处理的斑马鱼的体重(上图)及体内葡萄糖(下图)。#:P<0.05;##:P<0.01;***:P<0.001。(统计标记***是指第13天与第0天体重之间的比较。)
图4所示为于第13天以qPCR检测经AMS5处理的斑马鱼的MPX、IL10、CD86、IL4的基因表现量。Y轴(-ΔΔCT)代表扩增阈值周期的差异。**:P<0.01;****:P<0.0001。
图5所示为通过如本文实施例4中揭示的胜肽处理减少斑马鱼的体重。于第0、1、3、6、9、12和13天测量斑马鱼的体重。
图6所示为于实施例4的第12天以本文揭示的胜肽处理的斑马鱼的体重(上图)及体内葡萄糖(下图)。****:P<0.0001。
图7所示为通过如本文实施例5中揭示的胜肽处理减少斑马鱼的体重。于第0、1、3、6、9、12,以及13天测量斑马鱼的体重。
图8所示为于实施例5的第13天以本文所述的胜肽处理的斑马鱼的体重(上图及中图)以及体内葡萄糖(下图)。*:P<0.05;**:P<0.01。
具体实施方式
当结合附图阅读时,做出以下实施例以清楚地展现本发明的上述及其他技术内容、特征及效果。由于本发明所揭示的内容应被本领域技术人员容易地理解并可实施,因此不背离本发明的概念的所有等同改变或修改应由所附权利要求书涵盖。
除非另有说明,否则本申请中使用的以下术语,包括说明书及权利要求书,具有以下给出的定义。
如说明书及所附权利要求书中所使用的,单数形式“一”、“一个”以及“该”包括复数对象,除非上下文另外明确指出。除非另有说明,否则采用蛋白质化学、生物化学、重组DNA技术,以及药理学的常规方法。在本申请中,“或”或“及”的使用表示“及/或”,除非另有说明。此外,术语“包括(动名词)”以及其他形式,例如“包括(动词)”、“包括(单数动词)”以及“包括(被动词)”的使用并非限制性的。本文使用的章节标题仅用于组织目的,而不应解释为限制所描述的主题。
本文可互换使用的“多胜肽”、“胜肽”以及“蛋白质”等词是指任何长度的胺基酸的聚合形式,其可包括天然存在的胺基酸、编码或非编码胺基酸、化学或生物化学修饰、衍生,或设计的胺基酸、胺基酸类似物、拟肽物,以及酯肽,以及具有修饰的、环状的、双环的、酯环的,或酯双环胜肽骨架。该术语包括单链蛋白以及多聚体。
“配体”一词是指与另一个分子结合的分子,包括受体。
如本文所用,“有效量”或“治疗有效量”等词是指所施用的足够量的药剂或化合物,其将在某种程度上减轻所治疗的疾病或病症的一种或多种症状。结果可为减少及/或减轻疾病的征状、症状,或原因,或生物系统的任何其他期望的改变。例如,用于治疗用途的一“有效量”为提供疾病症状的临床上显著减少所需的包含本文揭示的胜肽或蛋白质的组合物的量。于任何情况下,都可以使用例如剂量递增研究等技术确定适当的“有效”量。
如本文所用,“组合物”一词是指通过混合或组合超过一种活性成分所得到的产物,且包括该活性成分的固定及非固定组合。术语“固定组合”是指活性成分与某种辅助剂都以单一实体或剂量的形式同时施用于患者。术语“非固定组合”是指将活性成分与某种辅助剂作为分开的实体同步、同时或依次施用于患者,无特定的介入时间限制,其中这样的施用方式在患者体内提供两种化合物的有效程度。后者也适用于鸡尾酒疗法,例如施用三种或三种以上有效成分。
如本文所用,“组合物”一词亦指通常包含一医药上可接受的载剂的混合物,例如本领域常规的一医药上可接受的载剂或赋形剂。
如本文所用,“共同施用”一词等意在涵盖将选择的治疗剂施用于单一患者,且意在包括其中通过相同或不同途径的药剂依序或同时施用的治疗方案。
如本文所用,“载剂”一词是指相对无毒的化合物或试剂,其促进化合物掺入细胞或组织中。
医药上可接受的载剂可选自,例如,赋形剂、佐剂、稀释剂、填充剂或增积剂、制粒剂、涂覆剂、释放控制剂、粘合剂、崩解剂、润滑剂、防腐剂、抗氧化剂、缓冲剂、悬浮剂、增稠剂、调味剂、甜味剂、掩味剂、稳定剂,或任何其他医药组合物中通常使用的赋形剂。
合适的赋形剂的实例包括,但不限于,乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖、淀粉、阿拉伯树胶、磷酸钙、藻酸盐、黄芪胶、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮(polyvinylpyrrolidone,PVP)、纤维素、ddH2O、糖浆,或甲基纤维素。
“医药上可接受的载剂”是指任何常规类型的无毒固体、半固体或液体填充剂、稀释剂、包囊材料、制剂助剂,或任何常规类型的赋形剂。一医药上可接受的载剂在所采用的剂量及浓度下对受体无毒,且与制剂的其他成分相容。
本文所用的“治疗”等词包括减轻、缓和,或改善疾病或病症的至少一种症状、预防其他症状、抑制疾病或病症,例如,阻止疾病或病症的发展、缓解疾病或病症、引起疾病或病症消退、缓解由疾病或病症引起的病症,或预防性及/或治疗性地停止疾病或病症的症状。
本文使用的“疾病”一词是指需要医学干预或需要进行医学干预的任何症状、感染、病症,或症候群。这样的医学干预可包括治疗、诊断,及/或预防。
嗜黏液艾克曼菌为人类肠道粘蛋白降解细菌的一种,最早发现于2004年。嗜黏液艾克曼菌为一种革兰氏阴性、严格厌氧、无运动、无芽孢的椭圆形细菌。人们认为嗜粘液艾克曼菌对人类具有抗发炎作用,研究显示黏液艾克曼菌的拓殖与例如阑尾炎或发炎性肠道疾病(inflammatory bowel disease,IBD)等发炎性病症之间存在反比关系。
据信,人类肠道中的嗜粘液艾克曼菌的减少与某些病理状况高度相关,因此嗜粘液艾克曼菌为一种潜在的有益微生物,因为其可作为药物或营养食品的潜在用途。
Amuc_1100*为艾克曼菌的一种外膜蛋白,已经被确认并被发现其可活化肠上皮细胞类铎受体2(TLR2)调节的细胞内信号,进而有助于增强肠屏障。已经揭示了Amuc_1100*参与免疫反应,特别是诱导介白素10(interleukin-10,IL-10)的产生,IL-10为一种抗发炎细胞激素。
类铎受体(TLRs)为跨膜蛋白,包括13种,并在广泛的细胞及组织中表现,包括免疫活性细胞如巨噬细胞及嗜中性白血球、血管内皮细胞,以及肾内在细胞如肾小管上皮细胞。TLR的活化诱导发炎性细胞激素的表现,例如肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF-α)以及介白素6(IL-6),并通过例如活化核因子-κB(nuclear factor-kappa B,NF-κB)引起发炎反应,NF-κB为一种转录因子。已知这种TLR调节的各种细胞的活化涉及免疫发炎性疾病,例如败血症、急性肾衰竭、慢性肾病、急性呼吸窘迫症候群、硬皮病、急性胰腺炎,以及慢性阻塞性肺病。
类铎受体2,也称为“TLR2”,是指在人类中由TLR2基因编码的蛋白质。TLR2也被称为“CD282”(分化簇282)。TLR2为类铎受体的一种,并在免疫系统中具有作用。TLR2为一种膜蛋白、一种受体,在某些细胞的表面表现并识别异物,并将适当的信号传递给免疫系统的细胞。在肠道中,TLR2调节CYP1A1的表现,而CYP1A1为去除致癌多环芳烃(例如苯芘)毒性的关键酵素。
本文所用的“TLR2相关疾病”、“与TLR2有关的病症或疾病”等词是指与类铎受体2有关的任何疾病状态。这些疾病或病症包括但,不限于,传染性疾病、发炎性疾病、呼吸系统疾病,免疫性疾病,以及胃肠道及结肠直肠疾病。
在本发明的一些具体实施例中,与TLR2相关的疾病为肠上皮屏障功能障碍,例如发炎性肠道疾病、乳麋泻、腹泻病、第II型糖尿病、肥胖症,或非酒精性脂肪肝病(NAFLD)。因此,随着肠上皮屏障功能障碍的减轻,肠吸收的致癌物减少,且进一步降低了肠致癌物毒性并预防小肠癌。更进一步地,由于肠上皮屏障发生故障,与TLR2相关的疾病进一步与肥胖症有关。因此,与TLR2有关的疾病包括肥胖症。
本文所用的“肥胖症”一词是指体内脂肪的过度积累。
本文所用的对抗原或组合物的“免疫反应”或“免疫学反应”等词是指对一个体对该抗原或组合物的体液及/或细胞免疫反应的发展。
根据本发明,可以适合于口服、肠胃外、局部、鼻内、支气管内、舌下、直肠,或经皮施用的任何形式制备包含该胜肽的组合物或医药组合物。当该组合物打算用于肠胃外施用时,可将它们配制成静脉内、肌肉内、腹膜内、皮下施用或通过注射、输注或其他递送方式直接递送到目标器官或组织中。
适用于口服施用的医药剂型包括片剂、胶囊剂(硬壳或软壳)、胶囊型锭剂、丸剂、口含锭、糖浆、溶液、粉剂、颗粒、酏剂、悬浮剂、舌下锭、薄片,或贴剂,例如颊贴剂。
针对口服施用,细粉或颗粒可包含稀释剂、分散剂,及/或表面活性剂,可以水或糖浆形式存在、干燥状态的胶囊或小袋,或非水溶液或悬浮液形式存在,其中可包含悬浮剂,可以包含粘合剂及润滑剂的片剂,或在水或糖浆中的悬浮液。当需要或必要时,可包括调味剂、防腐剂、悬浮剂、增稠剂,或乳化剂。片剂及颗粒为较佳的口服施用形式,并可将其涂布。
本文揭示的医药组合物可通过冻干保存,并可在使用前与合适的载剂一起重建。冻干及重建可根据本领域普通技术进行,且技术人员将理解,冻干及重建导致一定程度的活性损失,且应当向上调整医药剂量以进行补偿。本文揭示的医药组合物也可通过例如喷雾干燥、转鼓干燥(Drum Drying)、或真空干燥的方法来制造,但不限于此。
如本文所定义,Amuc_1100是指蛋白质Amuc_1100的全长,可自通用资料库获得;本文定义的Amuc_1100*是指不包含其跨膜结构域的蛋白质Amuc_1100,且在本文中以SEQ IDNO:1表示。
根据本发明,于一些衍生自Amuc_1100的胺基酸片段的基础上设计了一些合成胜肽。具体而言,该合成胜肽包含选自由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组。
于一些具体实施例中,该胜肽具有至多50个胺基酸的长度。于一些具体实施例中,该胜肽具有至多40个胺基酸的长度。于一些具体实施例中,该胜肽具有至多30个胺基酸的长度。于一些具体实施例中,该胜肽具有至多20个胺基酸的长度。
于一些具体实施例中,本文所用的胜肽作为引发类铎受体(TLR),特别是TLR2,的下游信号的配体。
本文提供的一方面为与TLR2交互作用的合成胜肽,其包含由SEQ ID NO:8组成的胺基酸序列;但长度最多为50个胺基酸。
于一具体实施例中,该合成胜肽具有至多30个胺基酸的长度。
于一具体实施例中,该合成胜肽由SEQ ID NO:8的胺基酸序列所组成。
本文提供的另一方面为用于治疗TLR2相关疾病的组合物,包含医药上可接受的载剂,以及至少一包含SEQ ID NO:8所示片段的胜肽。
本文提供的另一方面为治疗TLR2相关疾病的方法,包含对一有需要的个体施用一治疗有效量的一合成胜肽,该合成胜肽包含由SEQ ID NO:8所组成的胺基酸序列。
于一具体实施例中,该合成胜肽经口服或肠胃外施用。
本文提供的另一方面为具有治疗肥胖症功效的合成胜肽,包含一选自由SEQ IDNO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组的胺基酸序列,但长度最多为50个胺基酸。
于一具体实施例中,该合成胜肽具有至多30个胺基酸的长度。
于一具体实施例中,该合成胜肽由SEQ ID NO:10的胺基酸序列组成。
于一具体实施例中,该合成胜肽由SEQ ID NO:8的胺基酸序列组成。
于一具体实施例中,该合成胜肽由SEQ ID NO:15的胺基酸序列组成。
于一具体实施例中,合成胜肽由SEQ ID NO:19的胺基酸序列组成。
于一具体实施例中,合成胜肽由SEQ ID NO:20的胺基酸序列组成。
本文提供的另一方面为用于治疗肥胖症的医药组合物,其包含医药上可接受的载体,以及至少一种胜肽,该胜肽包含选自由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组的一片段。
本文提供的另一方面为用于治疗肥胖症的方法,包含对一有需要的个体施用一治疗有效量的一合成胜肽,该合成胜肽包含由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的胺基酸序列。
于一具体实施例中,该合成胜肽经口服或肠胃外施用。
于一具体实施例中,该合成胜肽提供促进免疫反应的功效。
于一具体实施例中,该胜肽与一疫苗共同施用并作为佐剂。
本文提供的另一方面为预防小肠癌及减少肠致癌物毒性的方法,包含对一有需要的个体施用一治疗有效量的包含本文所揭示的胜肽的一分离的胜肽。
于一具体实施例中,该合成胜肽经口服或肠胃外施用。
本文提供的另一方面为一种治疗由肠上皮屏障功能障碍引起的疾病的方法,该方法包含对一有需要的个体施用一治疗有效量的如本文所揭示的胜肽。
于一具体实施例中,由肠上皮屏障功能障碍引起的疾病为发炎性肠道疾病、乳麋泻、腹泻病、第II型糖尿病、肥胖症,或非酒精性脂肪肝病(NAFLD)。
实施例
实施例1.Amuc_1100*的裂解胜肽的制备
Amuc_1100*的全长基本上包含317个胺基酸,约17,384kDa(SEQ ID NO:1)。
Amuc_1100*也可以分为如下表1所示的片段。
表1
名称 | 序列识别号 | 序列 |
AMS1 | SEQ ID NO:2 | IVNSKRSELDKKISIAAKEIKSANAAEITPSR |
AMS2 | SEQ ID NO:3 | SSNEELEKELNRYAKAVGSLETAYKPFLASSA |
AMS3 | SEQ ID NO:4 | LVPTTPTAFQNELKTFRDSLISSCKKK |
AMS4 | SEQ ID NO:5 | NILITDTSSWLGFQVYSTQAPSVQAASTLGFELK |
AMS4-1 | SEQ ID NO:6 | NILITDTSSWLGFQVY |
AMS4-2 | SEQ ID NO:7 | STQAPSVQAASTLGFELK |
AMS5 | SEQ ID NO:8 | AINSLVNKLAECGLSKFIKVYRPQL |
AMS5-1 | SEQ ID NO:9 | AINSLVNKLAEC |
AMS5-2 | SEQ ID NO:10 | GLSKFIKVYRPQL |
AMS6 | SEQ ID NO:11 | PIETPANNPEESDEADQAPWTPMP |
AMS7 | SEQ ID NO:12 | LEIAFQGDRESVLKAMNAITGMQDYLF |
AMS7-1 | SEQ ID NO:13 | LEIAFQGDRESVLK |
AMS7-2 | SEQ ID NO:14 | AMNAITGMQDYLF |
AMS8 | SEQ ID NO:15 | TVNSIRIRNER |
AMS9 | SEQ ID NO:16 | MMPPPIANPAAAKPAAAQPATGAASL |
AMS10 | SEQ ID NO:17 | TPADEAAAPAAPAIQQVIKPYMGK |
AMS11 | SEQ ID NO:18 | EQVFVQVSLNLVHFNQPKAQEPSED |
AMS11-1 | SEQ ID NO:19 | EQVFVQVSLNL |
AMS11-2 | SEQ ID NO:20 | VHFNQPKAQEPSED |
表1中列出的胜肽的产生及纯化包含以下步骤。
表现质体源自具有Amuc_1100*片段的pET28a。在大肠杆菌中表现时,将片段选殖到麸胺基硫S-转移酶(GST)的C端以形成融合蛋白。将细菌培养物在LB培养基中培养,然后于中期指数阶段在生长培养基中添加1mM IPTG进行诱导。IPTG诱导3小时后,将细菌离心沉淀,并保存于-20℃下。
将细菌重新悬浮,并以溶菌酶及通过超音波裂解。离心后收集上清液,并在自然条件下使用ABT的麸胺基硫树脂通过金属亲和纯化作用纯化所需的胜肽片段。使用10K蛇皮透析管柱在0.1x PBS中进行缓冲液交换后,以BCA分析确认流洗的胜肽,并将胜肽样品保存于-20℃下。
纯化后,使用Biorad的CHTTM陶瓷羟基磷灰石微珠从流洗的胜肽中去除内毒素。使用LAL(鲎阿米巴样细胞裂解物,Limulis Amebocyte Lysate)套组进行内毒素检测,以确认内毒素的去除。所有胜肽样品中的内毒素均在10EU/mL下测量。
实施例2
以本文揭示的胜肽片段处理人类胚胎肾细胞293(HEK-293)。
在重组HEK-293细胞株上测试样品及对照,并进行二重复。这些细胞株在功能上过表现人类TLR以及一种报导基因,该基因为一种分泌的碱性磷酸酶(secreted alkalinephosphatase,SEAP)。该报导基因的产生是由NF-κB诱导型启动子驱动的。活化程度以光密度值(OD)表示。
将100μg/ml的样品稀释至反应体积中的最终浓度为10μg/ml。样品及对照在重复的孔中进行测试。BSA作为阴性对照。
SEAP报导子以OD值检测。OD值减去平均非诱导(NI)值。将NI减去的重复项取平均值并以直方图表示。本实施例中使用的试剂及材料由Invivogen提供。
图1所示为本文揭示的胜肽对TLR诱导的筛选。如图1A所示,人类类铎受体(TLR)对AMS5的反应为强烈而特异性地活化。而空白对照显示,TLR不活化报导基因的HEK-293对本文所述的任何胜肽的处理均无反应(图1B)。
因此,可结论出AMS5能够活化TLR2,而Amuc_1100的其他片段则不能。因此,AMS5为TLR2相关疾病的潜在药物。
实施例3:肥胖症的治疗
斑马鱼在许多报告中已长期作为肥胖的模型(Hasumura等人Nutrition&Metabolism(2012年);Tainaka等人Nutrition&Metabolism(2011年);Oka等人BMCPhysiology(2010年);Shimada等人Nutrition&Metabolism(2015年);Meguro等人Scientific Reports(2019年);Montalbano等人Endocrine(2018年);Yang等人Cancer(2019年)),斑马鱼在本文中并作为以本文所揭示的胜肽治疗肥胖症的对象。
通过CHT微珠纯化本实施例中使用的所有胜肽以去除内毒素。进一步进行LAL测定,证实内毒素的残留量低于0.25EU/ml。
将斑马鱼在25℃的水中(pH 6.5-7.5,导电率250-750S·m-1,NH3<0.25ppm,NO2<0.25ppm,NO3<0.5ppm)进行饲养,并喂饲正常的日粮(丰年虾)。每组实验包括10条斑马鱼(n=10)。
斑马鱼的管饲喂食遵循Collymore等人(Journal of Visualized Experiment(2013年))中揭示的方法。在实验的13天中,斑马鱼每天以0.03μg/天/鱼的1倍剂量喂饲本文所揭示的胜肽片段。在第0、1、3、6、9、12,以及13天分别测量斑马鱼的重量。于本实施例中,五组斑马鱼与本文所述的胜肽一起施用:
第1组:AMS4-1+AMS4-2
第2组:GST(空白)
第3组:AMS1+AMS2
第4组:AMS3+AMS9
第5组:AMS5
图2所示为斑马鱼体重变化的结果。如图2所示,在第5组中以AMS5给药的斑马鱼体重显著降低。经过13周的实验,斑马鱼服用AMS5后平均减少了约20mg。相反,其余组中的斑马鱼并未显示出体重的减少。
图3所示为实验结束时(第13天)斑马鱼的体重分布,其中施用AMS5的斑马鱼的体重降低显示出统计学意义。但是,斑马鱼血清中检测到的葡萄糖并未降低(图3,下图)。
此外,进行反转录(reversed-transcription,RT)-qPCR以检测根据本实施例的以AMS5处理的斑马鱼中MPX、IL10、CD86,以及IL4的基因表现量。在实验结束时(第13天),IL10与IL4的基因表现明显降低,而MPX与CD86的基因表现则未降低。
可结论出胜肽片段AMS5能够显著降低斑马鱼的体重,而体重的降低与IL10及IL4表现程度的降低有关,这代表发炎反应得到了抑制。
实施例4
本实施例中采用的材料及方法与实施例3相似,除了以下差异处外,其余不再赘述。
于本实施例中,五组斑马鱼与本文所述的胜肽一起施用:
第1组:AMS11-2
第2组:AMS11-1
第3组:AMS8
第4组:AMS5-2
第5组:GST(空白)
除GST(空白)处理外,所有组别的斑马鱼体重均显著降低(图5)。此外,相较于对照组(GST),斑马鱼的体重保持在原始程度,并在施用本文所用的胜肽后葡萄糖的含量没有改变(图6)。
实施例5
本实施例中采用的材料及方法与实施例3相似,除了以下差异处外,其余不再赘述。
于本实施例中,斑马鱼被饲养并每天喂饲6次正常的日粮(丰年虾),并且每天喂饲一次本文所揭示的胜肽,以诱导一种自发动物模型。
于本实施例中,五组斑马鱼与本文所述的胜肽一起施用:
第1组:AMS5-2
第2组:Amuc_1100*
第3组:GST(空白)
除GST(空白)处理外,所有组别中的斑马鱼的体重均显著降低(图7)。
此外,如图8所示,在实验结束时(第13天),相较于原始程度及GST组,经AMS5-2及Amuc_1100*处理的斑马鱼体重进一步减少。此外,观察到以AMS5-2及Amuc_1100*处理的组别中的葡萄糖含量降低(图8,下图)。
尽管已经在本文中显示出并描述本发明的较佳实施例,但对于本领域技术人员而言显而易见的是,仅通过示例的方式提供这样的实施例。在不脱离本发明的情况下,本领域技术人员现在将想到许多变化、改变及替换。应该理解的是,本文描述的本发明的具体实施例的各种替代方案可用于实施本发明。意图是,以下权利要求限定本发明的范围,并且由此涵盖这些权利要求范围内的方法与结构及其等同物。
序列表
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Claims (22)
1.一种与TLR2交互作用的合成胜肽,包含一由SEQ ID NO:8所组成的胺基酸序列;但长度最多为50个胺基酸。
2.如权利要求1所述的胜肽,其中该合成胜肽具有至多30个胺基酸的长度。
3.如权利要求1所述的胜肽,由SEQ ID NO:8的胺基酸序列组成。
4.一种用于治疗TLR2相关疾病的医药组合物,包含一医药上可接受的载剂,以及至少一包含如SEQ ID NO:8所述的一片段的胜肽。
5.一种TLR2相关疾病的治疗方法,包含对一有需要的个体施用一治疗有效量的一合成胜肽,该合成胜肽包含一由SEQ ID NO:8组成的胺基酸序列。
6.如权利要求5所述的方法,其中该合成胜肽经口服或肠胃外施用。
7.一种具有治疗肥胖症功效的合成胜肽,包含一选自由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组的胺基酸序列,但长度最多为50个胺基酸。
8.如权利要求7所述的胜肽,其中该合成胜肽具有至多30个胺基酸的长度。
9.如权利要求7所述的胜肽,由SEQ ID NO:10的胺基酸序列组成。
10.如权利要求7所述的胜肽,由SEQ ID NO:8的胺基酸序列组成。
11.如权利要求7所述的胜肽,由SEQ ID NO:15的胺基酸序列组成。
12.如权利要求7所述的胜肽,由SEQ ID NO:19的胺基酸序列组成。
13.如权利要求7所述的胜肽,由SEQ ID NO:20的胺基酸序列组成。
14.一种用于治疗肥胖症的医药组合物,包含一医药上可接受的载剂,以及至少一种胜肽,该胜肽包含选自由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的群组的一片段。
15.一种治疗肥胖症的方法,包含对一有需要的个体施用一治疗有效量的一合成胜肽,该合成胜肽包含由SEQ ID NO:10、SEQ ID NO:15、SEQ ID NO:19,以及SEQ ID NO:20所组成的一胺基酸序列。
16.如权利要求15所述的方法,其中该胜肽经口服或肠胃外施用。
17.如权利要求15所述的方法,其中该合成胜肽提供促进免疫反应的功效。
18.如权利要求17所述的方法,其中该胜肽与一疫苗共同施用并作为一佐剂。
19.一种预防小肠癌并减少小肠致癌物毒性的方法,包含对一有需要的个体施用一治疗有效量的一分离的胜肽,该分离的胜肽包含如权利要求1所定义的胜肽。
20.如权利要求19所述的方法,其中该合成胜肽经口服或肠胃外施用。
21.一种治疗一由肠上皮屏障功能障碍引起的疾病的方法,包含对一有需要的个体施用一治疗有效量的如权利要求1所定义的胜肽。
22.如权利要求21所述的方法,其中该由肠上皮屏障功能障碍引起的疾病为发炎性肠道疾病、乳麋泻、腹泻病、第II型糖尿病、肥胖症,或非酒精性脂肪肝病(non-alcoholicfatty liver disease,NAFLD)。
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