CN117050142A - 一种靶向卵巢的多肽及其衍生物和应用 - Google Patents
一种靶向卵巢的多肽及其衍生物和应用 Download PDFInfo
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Abstract
本发明公开了一种靶向卵巢的多肽及其衍生物的应用,属于生物医药领域。具体公开了本发明所述的多肽及其衍生物具有靶向卵巢的作用,还证明了其在制备治疗的卵巢相关生殖疾病、防治卵母细胞在体内或体外老化的药物或试剂中的用途。上述疾病包括月经周期紊乱、多囊卵巢综合征、雄化表型、毛发脱落、代谢异常、卵巢功能不全、卵巢早衰、排卵障碍、糖代谢异常、脂代谢异常,更优选为高血糖、胰岛素抵抗等。此外,本发明的多肽有望在辅助生殖领域延长卵母细胞或受精卵的保存时间和保存质量。
Description
技术领域
本发明属于医学生物学领域,涉及一种卵巢靶向多肽及其衍生物和应用。
背景技术
卵巢是女性非常重要的生殖器官,由生殖细胞(卵母细胞或卵子)和体细胞(颗粒细胞、膜细胞和基质细胞)组成,它们的相互作用决定了卵巢的功能,即分泌对卵泡发育、月经/发情周期和维持内分泌健康所必须的激素与产生成熟的卵子以供受精来产生后代。卵巢功能的异常会导致一系列卵巢生殖疾病如卵巢早衰(Premature Ovarian Failure,POF)、多囊卵巢综合症(Polycystic Ovary Syndrome,PCOS)、排卵障碍甚至卵巢癌(Ovarian Cancer,OC)的发生。
卵巢生殖疾病会导致机体激素紊乱,表现出一系列糖脂代谢异常如肥胖、胰岛素抵抗、脂肪肝、骨质疏松等;生殖异常如卵泡过度激活、排卵减少、不孕;衰老现象如更年期症状提前等。雌性体内高雄激素会导致一系列雄化表型如多毛、痤疮、脱发等,而高雌激素会导致一系列如卵巢癌、乳腺癌、子宫内膜癌等生殖肿瘤疾病的多发,严重危害女性身心健康和生命安全。
卵母细胞成熟后受精的窗口期非常有限。例如,小鼠最佳受精和发育的时间是排卵后不12小时内,而人类在排卵或取卵后4-12小时内。随时间推移,排出的卵母细胞进入老化阶段,最终凋亡不能进行受精。同时,在辅助生殖干预中,抑制哺乳动物排卵后老化可改善与提高受精率与生育率。
目前,针对卵巢生殖细胞和内分泌紊乱相关疾病的治疗主要有药物治疗、手术治疗和辅助生育技术。针对药物治疗方面,最大的问题是无法靶向治疗,药物作用于全身,可能对机体其他组织器官产生各种副作用;针对手术治疗和辅助生殖技术方面,除了成功率较低以外,还缺乏治疗后对卵巢发育情况较为清晰的无创实时观察。因此,筛选出能够在体内特异性靶向卵巢的多肽,研究其在卵巢生殖疾病中的作用以及作为靶向治疗卵巢生殖疾病的药物载体,具有重要的社会意义和广阔的经济市场。
发明内容
就上述背景技术中所提出的针对卵巢生殖疾病的治疗瓶颈问题,本发明的目的在于提供一种卵巢靶向多肽及其衍生物的功能和应用。
本发明发现了以下序列多肽,这些多肽能特异性靶向卵巢并缓解多种因为激素紊乱导致的卵巢相关生殖疾病、代谢异常和衰老引发的症状。
本发明一个方面提供了一种多肽,所述多肽序列包含式M1-Za-M2所示的序列或Za所示的序列,其中:
M1、M2各自独立地单个或多个氨基酸多肽区段或者不存在;
Za为Tyr-Leu-X1-X2-X3-X4-Gly-Ala-X5-X6-Pro-X7-Pro-Asp-X8-Leu-Glu-Pro-Thr
X1为Asn或Tyr或Asp或不存在,
X2为Asn或Gln或His或Pro或Ser或不存在,
X3为Gly或Trp或不存在,
X4为Leu或不存在,
X5为Pro或Ser,
X6为Ala或Val,
X7为Tyr或Ser或Ala,
X8为Pro或Thr,
进一步地,其中Za选自其中之一:
YLGASVPSPDPLEPT SEQ ID No.1;
YLNNGLGAPAPYPDPLEPT SEQ ID No.2;
YLYQWLGAPVPYPDPLEPT SEQ ID No.3;
YLYQWLGAPVPYPDTLEPT SEQ ID No.4
YLYQWLGAPAPYPDPLEPT SEQ ID No.5
YLDHWLGAPAPYPDPLEPT SEQ ID No.6
YLDPGLGAPAPYPDPLEPT SEQ ID No.7
YLDHGLGAPAPYPDPLEPT SEQ ID No.8
YLDQGLGAPAPAPDPLEPT SEQ ID No.9
YLDSGLGAPVPYPDPLEPT SEQ ID No.10
本发明另一方面提供了一种靶向卵巢多肽的衍生物,所述衍生物为所述多肽氨基酸侧链基团上、氨基端、羧基端进行常规修饰得到的产物,或者为多肽上连接用于多肽或蛋白检测或纯化的标签所得到的产物,或经过同位素标记修饰得到的产物;所述的常规修饰为荧光基团修饰、磷酸化修饰、二硫键的环化修饰、经过生物素标记修饰、光敏剂、叠氮修饰、PEG修饰、甲基化修饰、荧光淬灭基团修饰、蛋白偶联修饰、小分子化合物修饰、氨基化修饰、酰胺化修饰、羟基化修饰、羧基化修饰、羰基化修饰、烷基化修饰、乙酰化修饰、酯化修饰、糖基化修饰;
进一步地,所述的标签为His6、GST、EGFP、MBP、Nus、HA、IgG、FLAG、c-Myc或ProfinityeXact。
进一步地,所述氨基端、羧基端的修饰选自多肽N端乙酰化修饰和C端的胺化修饰。
进一步地,所述侧链的修饰选自多肽中氨基酸侧链R基上的修饰。
进一步地,所述荧光基团的修饰中所用的荧光染料选自AMCA、FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7、AIE、ICG,该修饰可用于荧光检测。
进一步地,所述磷酸化修饰选自p-Ser、p-Thr、p-Tyr中的一种或多种的组合。
进一步地,所述糖基化修饰选自Ser、Asn、Thr、Tyr中的一种或多种的组合。
进一步地,所述硝基化修饰选自Tyr中的一种或多种的组合。
进一步地,所述生物素的标记,所述生物素选自D-生物素、生物素酰肼、光敏生物素和生物素-dUTP。
进一步地,所述光敏剂修饰,可用于制备光敏感制剂。
进一步地,所述叠氮修饰,可用于次级的连接反应。
进一步地,所述PEG修饰,可用于制备药物载体。
进一步地,所述同位素标记中所用的同位素选自13C、14C、14N、15N、2H、3H、18O、32P、32S、34S、35S、36S、35Cl、37Cl、125I、131I中的一种或多种的组合。
本发明再一个方面提供了一种多聚核苷酸,其编码上述多肽或其衍生物。
本发明再一个方面提供了一种载体,其包含了上述多聚核苷酸。
本发明再一个方面提供了一种宿主细胞,其转染了上述载体。
本发明再一个方面提供了本发明所述多肽或其衍生物在制备靶向卵巢的检测试剂、靶向卵巢的药物或靶向卵巢的工具中的用途。
进一步地,所述工具选自载体或制剂,例如通过偶联本发明所述多肽或其衍生物实现靶向效果的载体、制剂或试剂盒,制剂如脂质体、纳米粒等。
本发明另一个方面提供了上述多肽或其衍生物在制备能够靶向卵巢的药物或检测试剂中的用途。
进一步地,所述药物和检测试剂包括上述多肽及以其为骨架的衍生物,作为抗原制备的检测产品如检测试剂、试剂盒、试纸条。
本发明另一个方面提供了一种靶向卵巢的载体,上述多肽及以其为骨架的衍生物可作为靶向治疗卵巢相关生殖疾病的工具。
进一步地,所述载体选自脂质体、纳米粒、外泌体、生物可降解高分子物质、抗体-配体。
进一步地,所述载体中含有可治疗卵巢相关生殖疾病的成分。
所述的多肽及以其为骨架的衍生物可通过一般化学实验室条件自主合成,可通过基因表达出来的含有上述多肽的重组蛋白,也可以由商业化试剂公司工业合成,采用固相法合成多肽,在树脂上不同氨基酸,经过缩合反应定向合成氨基酸链。多肽的衍生物,是在氨基酸完成连接后,再标记上修饰基团。
本发明再一方面提供了一种靶向卵巢的药物,所述药物为上述多肽及以其为骨架的衍生物与活性成分的偶联物。所述的多肽及以其为骨架的衍生物可通过靶向卵巢治疗因生殖细胞异常和激素紊乱导致的生殖、代谢及衰老相关疾病。
本发明再一方面提供了一种靶向卵巢的多肽探针,所述多肽探针为上述多肽或以其为骨架的衍生物,与荧光染料通过有机化学反应偶联制得。
进一步地,所述荧光染料选择具有近红外区荧光基团的染料,优选地,所述具有近红外区荧光基团的染料选自AIE、Cy5、Cy7、ICG。
本发明再一方面提供了所述多肽在制备治疗的卵巢相关生殖疾病的药物或试剂中的用途。
进一步地,卵巢相关生殖疾病选自生殖细胞异常或激素紊乱导致的卵巢相关生殖疾病。
进一步地,所述激素紊乱为雄性激素超过正常水平。
进一步地,所述生殖细胞异常导致的卵巢相关生殖疾病为由于卵母细胞老化,和或卵母细胞透明袋硬化导致的卵巢相关生殖疾病,优选地为所述的生殖细胞异常导致的卵巢相关生殖疾病选自卵母细胞数量异常、卵母细胞质量下降和卵子老化。
进一步地,所述的因激素紊乱导致的卵巢相关生殖疾病包括月经周期紊乱、多囊卵巢综合征、雄化表型、毛发脱落、代谢异常、卵巢功能不全、卵巢早衰、和排卵障碍。
进一步地,所述的因激素紊乱导致的代谢异常选自糖代谢异常、脂代谢异常,优选为高血糖、胰岛素抵抗、肥胖、脂肪肝、骨质疏松。
进一步地,雄化表型选自痤疮、多毛、脱发。
进一步地,所述的因激素紊乱导致的衰老及相关症状包括围绝经期、更年期综合征、衰老、痤疮、长痘、多毛、脱发。
本发明再一方面提供了所述多肽在制备防治卵母细胞在体内或体外老化的药物或试剂中的用途。
本发明再一方面提供了一种辅助生殖用品,其包括本发明所述的多肽或其衍生物。
进一步地,所述辅助生殖用品为辅助生殖过程中卵母细胞和或受精卵的保护液。
本发明再一方面提供了上述辅助生殖用品在制备辅助生殖过程中用于保存卵母细胞和或受精卵的保护液中的用途。
本发明的有益效果:
(1)本发明提供的候选多肽及以其为骨架的衍生物,可以在体内外特异性靶向卵巢。
(2)本发明提供的候选多肽及以其为骨架的衍生物,可作为修饰多肽以增强药物或药物载体对卵巢的靶向性和干预及治疗效果。
(3)本发明提供的候选多肽及以其为骨架的衍生物,其易于合成修饰,成本低廉,因此应用前景广泛。
(4)本发明提供的候选多肽及以其为骨架的衍生物,为其实际应用提供了广泛的诊疗化合物或药物的制备策略。
(5)本发明提供的候选多肽及以其为骨架的衍生物,适用于靶向治疗卵巢相关生殖疾病的应用,也适用于作为卵巢疾病造模实验动物中的研究和观察工具。
附图说明
图1为连接ICG后的多肽在体内靶向卵巢的效果图。图中显示了PBS组、ICG组和ICG连接多肽组三组小鼠卵巢和子宫的荧光信号分布和结果。
图2为连接AIE后的多肽在体内靶向卵巢的效果图。图中显示了PBS组、AIE空颗粒组、AIE连接多肽组和AIE连接其他多肽组四组小鼠卵巢的荧光信号分布和结果。
图3为连接AIE后的多肽在体内靶向卵巢的定位图。图中显示了PBS组、AIE空颗粒组、AIE连接多肽组和AIE连接其他多肽组四组小鼠卵巢的荧光信号定位。其中,箭头指示膜细胞,星号指示间质细胞。
图4为靶向卵巢多肽在高雄激素-双氢睾酮(DHT)诱导的小鼠模型中,对高雄激素导致的卵泡发育异常、动情周期紊乱、小鼠雄化表型和血糖异常的缓解作用。图4A是对照组、DHT组和DHT+靶向卵巢多肽组三组小鼠卵巢形态学观察。图4B是三组小鼠十天中的动情期天数。图4C是造模60天后,小鼠肛殖区距离(雄性肛殖区距离较大)。图4D是造模60天后,小鼠口服葡萄糖后血糖变化。
图5为靶向卵巢多肽在高雄激素-双氢睾酮(DHT)诱导的小鼠模型中,对高雄激素导致的体重变化的缓解作用。图5A是体重变化,图5B是体重增长量的变化。图5C是性腺脂肪的重量变化,图5D是除脂肪外的瘦体重变化。
图6为靶向卵巢多肽在高雄激素-双氢睾酮(DHT)诱导的小鼠模型中,对高雄激素导致的小鼠颈背部毛发脱落的影响。图6A是对照组、DHT组和DHT+靶向卵巢多肽组三组小鼠颈背部毛发脱落现象的观察。图6B是三组小鼠颈背部皮肤雄激素受体AR表达的免疫荧光图。
图7为靶向多肽在卵母细胞排卵后老化模型中,对老化导致的卵母细胞碎裂与退化、透明带硬化与体外受精情况的改善作用。图7A是对照组、老化组和靶向多肽组老化12小时后退化与碎裂率。图7B是对照组、老化组和靶向多肽组老化12小时透明带硬化水平。图7C是对照组、老化组和靶向多肽组体外老化12小时后体外受精率。
图8为OCN15 KO小鼠在超排模型中与WT小鼠相比的血清雌孕激素水平变化。图8的左图为超排过程中雌激素水平变化。图8的右图是超排过程中孕激素水平变化。
图9为靶向卵巢多肽在高雄激素-双氢睾酮(DHT)诱导的小鼠模型中,对高雄激素导致的小鼠肝脏脂滴积累的影响。
图10为不同物种来源的代谢素的序列对比图。
具体实施方式
为了更好地理解本发明的内容,下面结合具体实施案例,对本发明内容作进一步说明,但本发明的保护内容不局限以下实施例。
除非另外特别指出,否则本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。此外,与本文描述的方法或材料类似或等同的任何方法或材料可用于实施本发明。出于本发明的目的,定义了以下术语。
术语“受试者”、“个体”和“患者”在本文中可互换使用以指脊椎动物,优选哺乳动物。哺乳动物包括但不限于人类、小鼠、大鼠、黑猩猩、猕猴、牛、绵羊、野猪、鼹鼠、狗。还涵盖了在体内获得或在体外培养的生物实体的组织、细胞及其后代。
如本文所用,术语“施用”包括经口施用、局部接触、作为栓剂施用、静脉内、腹膜内、肌内、病灶内、鞘内、鼻内或皮下施用给受试者。施用是通过任何途径,包括肠胃外和经粘膜(如,经颊、舌下、经腭、经牙龈、经鼻、经阴道、经直肠或经皮)。肠胃外施用包括如,静脉内、肌内、动脉内、皮内、皮下、腹膜内、心室内和颅内。其他的递送模式包括但不限于使用脂质体制剂、静脉内输注、经皮贴剂等。
术语“治疗”是指用于获得包括但不限于治疗性益处在内的有益或期望结果的方法。治疗性益处意指治疗中的一种或多种疾病、病况或症状的任何治疗相关的改善,或对治疗中的一种或多种疾病、病况或症状的任何治疗相关的作用。“预防”是指用于获得包括但不限于预防性益处在内的有益或期望结果的方法。对于预防性益处,组合物可以施用给具有发展特定疾病、病况或症状风险的受试者,或施用给报告疾病的一种或多种生理症状的受试者,即使所述疾病、病况或症状可能尚未表现出来。
术语“治疗有效量”是指肽或组合物的足以实现有益或所需结果的量。治疗有效量可以取决于以下一个或多个而变化:被治疗的受试者和疾病状况、受试者的体重和年龄、疾病状况的严重程度、施用方式等,其可以由本领域普通技术人员容易地确定。具体的量可以取决于以下一个或多个而变化:所选择的特定药剂、靶细胞类型、受试者体内靶细胞的位置、要遵循的给药方案、是否与其他化合物联合施用、施用的时间以及携带它的实体递送系统。
实施例1:多肽序列的制备
采用人工合成的方法合成多肽序列,
所述多肽序列如下所述:
YLGASVPSPDPLEPT SEQ ID No.1;
YLNNGLGAPAPYPDPLEPT SEQ ID No.2;
YLYQWLGAPVPYPDPLEPT SEQ ID No.3;
YLYQWLGAPVPYPDTLEPT SEQ ID No.4
YLYQWLGAPAPYPDPLEPT SEQ ID No.5
YLDHWLGAPAPYPDPLEPT SEQ ID No.6
YLDPGLGAPAPYPDPLEPT SEQ ID No.7
YLDHGLGAPAPYPDPLEPT SEQ ID No.8
YLDQGLGAPAPAPDPLEPT SEQ ID No.9
YLDSGLGAPVPYPDPLEPT SEQ ID No.10
采用常规的固相合成或液相合成的方法合成上述多肽。其中利用固相合成多肽法为从C端的氨基酸向N端反应,经过树脂活化、氨基酸链接、洗脱保护、检测等步骤,逐个完成氨基酸链接,然后用过量乙醚沉淀离心,对粗肽经过HPLC纯化后,质谱分析,在液氮中速冷冻干备用。
在本发明中,所述的肽均为分离的肽。
其中SEQ ID NO.1为小鼠代谢素,SEQ ID NO.2为大鼠代谢素,SEQ ID NO.3为人源代谢素,SEQ ID NO.4为黑猩猩代谢素,SEQ ID NO.5为猕猴代谢素,SEQ ID NO.6为牛代谢素,SEQ ID NO.7为绵羊代谢素,SEQ ID NO.8为野猪代谢素,SEQ ID NO.9为鼹鼠代谢素,SEQ ID NO.10为狗代谢素(如图10所示)。
实施例2:多肽探针的制备
本实施例提供一种多肽探针,采用实施例1制备的多肽,将其与ICG/AIE通过有机化学反应结合。
具体方法为委托合成或自行合成,本实施例中,通过点击化学方法将多肽与ICG或AIE连接完成探针制备,其中的连接子为通用的DBCO。具有活化功能基团的ICG/AIE,活化功能基团包含氨基NH2、羧基COOH、活化脂NHS、马来酰亚胺MAL、巯基SH、叠氮N3、炔烃ALK,然后与实施例1制备的多肽偶联,获得多肽ICG/AIE探针。
实施例3:多肽ICG探针靶向小鼠卵巢能力检测
成年小鼠尾静脉注射实施例2制备的多肽ICG探针(含SEQ ID NO.1)溶液、ICG溶液(2mM)以及PBS,每只小鼠注射100μL,24小时后,在小动物成像仪下检测。
实验结果见图1,通过对比3组结果可知,在卵巢部位多肽ICG探针组(OCN15-ICG,含SEQ ID NO.1的ICG探针)有特异信号,而其他两组(ICG溶液组和PBS组)均未显示在卵巢部位有荧光信号。
以上实验结果可知,本发明的多肽对卵巢有特异性响应,能够实现在体内靶向卵巢的作用。
实施例4:多肽AIE探针靶向小鼠卵巢能力检测
成年小鼠尾静脉注射实施例2制备的多肽AIE探针(含SEQ ID NO.1)、乱序多肽AIE探针、AIE空颗粒以及PBS,每只小鼠注射100μL,24小时后,在小动物成像仪下检测。
实验结果见图2,通过对比4组结果可知,在卵巢部位多肽AIE探针组(OCN15,含SEQID NO.1的AIE探针)有特异信号,乱序多肽AIE探针组(OCN22)和PBS组均未显示在卵巢部位有荧光信号,AIE空颗粒组(NP)有微弱的信号。
以上实验结果可知,本发明的多肽对卵巢有特异性响应,能够实现在体内靶向卵巢的作用。
通过对比实施例3和4可知,本发明多肽对卵巢有特异性响应,对其进行的修饰并不会影响其靶向作用,这预示着本发明多肽能够用于制备向卵巢靶向的药物、检测试剂或制剂等。
实施例5:多肽靶向小鼠卵巢的定位
为了进一步确定多肽靶向卵巢的定位,实施例4中的四组小鼠卵巢通过4%PFA固定后,冰冻切片(10μm),染细胞核(DAPI),在激光共聚焦显微镜下观察荧光定位。
实验结果见图3,其中,箭头指示膜细胞,星号指示间质细胞。
通过对比4组结果可知,多肽AIE探针组(OCN15-AIE)主要靶向小鼠卵巢间质细胞和膜细胞。
综上,本发明提供的介导多肽可用于卵巢靶向的目的,尤其是靶向卵巢中的卵巢间质细胞和膜细胞。对于多肽上的修饰并不会影响多肽的作用。
通过实施例5结果可以证明OCN15靶向卵巢间质细胞和膜细胞,可以结合下述实施例结果可以预期其应用于与这两种细胞异常相关的卵巢疾病,如高雄激素引起的膜细胞增厚和间质细胞增生、因膜细胞增厚和间质增生导致的排卵障碍、因排卵障碍导致的卵巢功能不全、月经周期紊乱和多囊卵巢综合征等。
实施例6:靶向卵巢多肽对高雄激素诱导的小鼠生殖和代谢症状的作用
野生型雌鼠在出生后的第25天(D25),随机分为:对照组(CTRL),DHT组,DHT+OCN15(OCT15即SEQ ID NO.1所示多肽)组,每组至少8只小鼠。对照组皮下埋植空泵,每天灌胃200μL生理盐水;DHT组皮下埋植含5mg二氢睾酮(DHT)粉末的缓释泵,每天灌胃200μL生理盐水;DHT+OCN15组皮下埋植含5mg DHT粉末的缓释泵,每天灌胃200μL含多肽的生理盐水(500μg/Kg),造模时间为60天。
实验结果见图4,通过对比3组小鼠可见,高雄激素会诱导小鼠卵巢出现多囊样改变和动情期减少。正常小鼠动情期天数为4天以上,而高雄组小鼠动情天数在2天作用,而同时使用OCN15能够在一定程度上缓解这些现象,动情天数接近3天,而多囊样改变也有所降低(图4A,B)。高雄激素会导致雌性小鼠出现雄化的现象,即肛殖区距离增加,而OCN15可以显著改善这一症状(图4C),可以将肛殖区距离恢复至与正常小鼠接近的程度,其中对照组与DHT组之间,以及DHT组与DHT+OCN15组之间显示了显著性差异。
血糖实验结果见图4D,血糖的峰值应该是在口服葡萄糖15分钟以后,30分钟的时候,对照组已下降,DHT组还是很高,与对照组的差异达3颗星,而OCN15处理后,与单独DHT组相比有显著下降,与对照组没有差异,说明OCN15让DHT诱导的在30min时的血糖异常趋于正常。
体重变化结果见图5,图5的A和B说明OCN15能够在一定程度上缓解DHT导致的小鼠体重和体重增加量的升高,主要减轻了小鼠性腺脂肪的重量(图5C)。OCN15联合DHT处理后的小鼠瘦体重是增加的,瘦体重主要是骨骼的重量,说明OCN15能够缓解因激素紊乱导致骨质疏松。
通过这个实施例结果可以证明OCN15可以应用于高雄激素导致的卵巢相关生殖疾病包括月经周期紊乱、多囊卵巢综合征和雄化表型,以及因激素紊乱导致的代谢异常如糖代谢异常、肥胖和骨质疏松。
此外,观察造模60天时小鼠毛发情况以及小鼠表皮层雄激素受体的表达情况。实验结果见图6,通过对比3组小鼠可见,高雄激素会导致小鼠颈背部皮肤的毛发出现脱落现象,而OCN15能够显著改善这一现象(图6A)。这可能是由于高雄激素导致雌性小鼠颈背部皮肤中表皮层雄激素受体AR表达的显著增加,进而导致毛发脱落,而OCN15能够显著降低DHT导致的雌性小鼠颈背部皮肤中表皮层雄激素受体AR表达的显著增加(图6B),这一结果也与小鼠颈背毛发脱落情况一致。
通过这个实施例结果可以证明OCN15可以应用于高雄激素导致的相关症状如女性脱发。
实施例7:靶向卵巢多肽对卵母细胞排卵后老化的作用
野生型雌性小鼠腹腔注射5IU PMSG(Pregnant Mare Serum Gonadotropin),48小时后腹腔注射5IU hCG(Human Chorionic Gonadotropin)进行超数排卵。14小时后收集卵母细胞,使用透明质酸酶去除卵丘细胞,随机分为Aging组与Aging+OCN15组并于M16培养液中培养老化。对照组(Control)老化时间0小时,Aging组老化时间12小时,Aging+OCN15组在含多肽的M16(1μg/mL)中老化12小时。
实验结果见图7,通过三组对比,OCN15可以改善卵母细胞体外老化所导致的碎裂与退化(图7A)。OCN15可以改善卵母细胞体外老化所导致的透明带硬化(图7B)。OCN15可以改善卵母细胞体外老化所导致的受精率低下,甚至与老化0小时受精率接近,没有显著性差异。
通过这个实施例结果可以证明OCN15可以应用于卵母细胞质量的保护,延缓其老化过程,改善因老化导致的受精率低下。可以应用于辅助生殖领域,提高卵母细胞以及受精卵的保存时间和保存质量。同时,可以预期由于其具有改善卵母细胞体外老化的作用,因此,可以用于卵母细胞由于老化导致的异常而诱发的疾病,例如卵母细胞数量异常、卵母细胞质量下降和卵子老化。
综上,本发明提供的介导多肽可用于增加卵母细胞受精窗口时间激素紊乱导致的卵巢相关生殖疾病、代谢异常和脱发等症状的治疗。
实施例8:靶向卵巢多肽敲除对小鼠超数排卵过程中血清激素水平的影响
野生型雌性小鼠和OCN15 KO小鼠腹腔注射5IU PMSG,48小时后腹腔注射5IU hCG进行超数排卵。在注射前、PMSG24h、PMSG48h、hCG12h分别处死小鼠,取血清检测性激素水平。
实验结果见图8,通过与WT小鼠的比较,可以发现超排过程中雌激素水平没有变化(图8的左图),而孕激素水平在PMSG48h时,OCN15 KO小鼠与WT小鼠相比显著升高(图8的右图)。PMSG48h这个时间点,是大部分卵泡被刺激发育到优势卵泡待排卵的阶段,而此阶段的孕激素主要是由大卵泡的颗粒细胞分泌,说明OCN15 KO小鼠在这一阶段与WT相比有更多的卵泡响应了PMSG的刺激,发育到待排卵阶段,因此OCN15 KO后可能导致小鼠卵泡过度激活,可能导致卵巢早衰,由此可以证明本发明的靶向卵巢多肽能够用于治疗卵巢早衰。
实施例9:靶向卵巢多肽对高雄激素诱导的小鼠肝脏脂滴积累的作用
高雄激素DHT诱导小鼠PCOS模型的方法见实施例6。造模结束后,取小鼠肝脏,4%多聚甲醛(PFA)固定过夜,酒精梯度脱水,石蜡包埋,切片(5um),HE染色做形态学观察。
实验结果见图9,通过与WT小鼠的肝脏形态比较,可以发现DHT模型小鼠肝脏细胞体积变大,提示胞质中更多的脂滴积累,而在DHT+OCN15处理组,这一现象被缓解。
由此证明本发明靶向卵巢多肽能够缓解高雄激素诱导的小鼠肝脏脂滴积累,用于治疗脂肪肝。
以上所述仅为本发明的具体实施方式,不是全部的实施方式,本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换,均为本发明的权利要求所涵盖。
SEQUENCE LISTING
<110> 中国科学院深圳先进技术研究院
<120> 一种靶向卵巢的多肽及其衍生物和应用
<130> CP122010286C
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Claims (12)
1.一种靶向卵巢的多肽,所述多肽序列包含式M1-Za-M2所示的序列或Za所示的序列,其中:
M1、M2各自独立地单个或多个氨基酸多肽区段或者不存在;
Za为Tyr-Leu-X1-X2-X3-X4-Gly-Ala-X5-X6-Pro-X7-Pro-Asp-X8-Leu-Glu-Pro-Thr
X1为Asn或Tyr或Asp或不存在,
X2为Asn或Gln或His或Pro或Ser或不存在,
X3为Gly或Trp或不存在,
X4为Leu或不存在,
X5为Pro或Ser,
X6为Ala或Val,
X7为Tyr或Ser或Ala,
X8为Pro或Thr,
优选地,其中Za选自其中之一:
2.一种靶向卵巢的多肽的衍生物,其特征在于,所述衍生物为权利要求1所述多肽氨基酸侧链基团上、氨基端、羧基端进行常规修饰得到的产物,或者为权利要求1多肽上连接用于多肽或蛋白检测或纯化的标签所得到的产物,或经过同位素标记修饰得到的产物;所述的常规修饰为荧光基团修饰、磷酸化修饰、二硫键的环化修饰、经过生物素标记修饰、光敏剂、叠氮修饰、PEG修饰、甲基化修饰、荧光淬灭基团修饰、蛋白偶联修饰、小分子化合物修饰、氨基化修饰、酰胺化修饰、羟基化修饰、羧基化修饰、羰基化修饰、烷基化修饰、乙酰化修饰、酯化修饰、糖基化修饰;
优选地,所述的标签为His6、GST、EGFP、MBP、Nus、HA、IgG、FLAG、c-Myc或ProfinityeXact;
优选地,所述氨基端、羧基端的修饰选自多肽N端乙酰化修饰和C端的胺化修饰;
优选地,所述侧链的修饰选自多肽中氨基酸侧链R基上的修饰;
优选地,所述荧光基团的修饰中所用的荧光染料选自AMCA、FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7、AIE、ICG,该修饰可用于荧光检测;
优选地,所述磷酸化修饰选自p-Ser、p-Thr、p-Tyr中的一种或多种的组合;
优选地,所述糖基化修饰选自Ser、Asn、Thr、Tyr中的一种或多种的组合;
优选地,所述硝基化修饰选自Tyr中的一种或多种的组合;
优选地,所述生物素的标记,所述生物素选自D-生物素、生物素酰肼、光敏生物素和生物素-dUTP;
优选地,所述同位素标记中所用的同位素选自13C、14C、14N、15N、2H、3H、18O、32P、32S、34S、35S、36S、35Cl、37Cl、125I、131I中的一种或多种的组合。
3.一种多聚核苷酸,其编码权利要求1所述多肽或权利要求2所述衍生物。
4.一种载体,其包含了权利要求3所述多聚核苷酸。
5.一种宿主细胞,其转染了权利要求4所述载体。
6.权利要求1所述多肽或权利要求2所述衍生物在制备靶向卵巢的检测试剂、靶向卵巢的药物或靶向卵巢的工具中的用途;
优选地,所述工具选自载体或制剂,更优选为通过偶联本发明所述多肽或其衍生物实现靶向效果的载体、制剂或试剂盒,更优选制剂为脂质体、纳米粒。
7.权利要求1所述多肽或权利要求2所述衍生物在制备能够靶向卵巢的药物或检测试剂中的用途;
优选地,所述药物和检测试剂包括权利要求1所述多肽和或权利要求2所述衍生物,作为抗原制备的检测产品,更优选地,所述检测产品为检测试剂、试剂盒、试纸条。
8.一种靶向卵巢的载体,其以权利要求1所述多肽和或权利要求2所述衍生物作为靶向剂;
优选地,所述载体选自脂质体、纳米粒、外泌体、生物可降解高分子物质、抗体-配体;
优选地,所述载体中含有可治疗卵巢相关生殖疾病的成分。
9.一种靶向卵巢的药物,所述药物为权利要求1所述多肽和或权利要求2所述衍生物与活性成分的偶联物。
10.一种靶向卵巢的多肽探针,所述多肽探针为权利要求1所述多肽和或权利要求2所述衍生物,与荧光染料通过有机化学反应偶联制得;
优选地,所述荧光染料选择具有近红外区荧光基团的染料,更优选地,所述具有近红外区荧光基团的染料选自AIE、Cy5、Cy7、ICG。
11.权利要求1所述多肽和或权利要求2所述衍生物在制备治疗的卵巢相关生殖疾病或缓解卵巢相关生殖疾病的症状的药物或试剂中的用途;所述卵巢相关生殖疾病选自生殖细胞异常导致的卵巢相关生殖疾病、激素紊乱导致的卵巢相关生殖疾病、因激素紊乱导致的衰老及相关症状;
或者在制备防止卵母细胞在体内或体外老化的药物或试剂中的用途;
优选地,所述激素紊乱为雄性激素超过正常水平;
优选地,所述生殖细胞异常导致的卵巢相关生殖疾病为由于卵母细胞老化,和或卵母细胞透明袋硬化导致的卵巢相关生殖疾病,更优选地,所述的生殖细胞异常导致的卵巢相关生殖疾病选自卵母细胞数量异常、卵母细胞质量下降和卵子老化;
优选地,所述的激素紊乱导致的卵巢相关生殖疾病选自月经周期紊乱、多囊卵巢综合征、雄化表型、毛发脱落、代谢异常、卵巢功能不全、卵巢早衰和排卵障碍;更优选地,雄化表型选自痤疮、多毛、脱发;
优选地,所述的因激素紊乱导致的代谢异常选自糖代谢异常、脂代谢异常,更优选为高血糖、胰岛素抵抗、肥胖、脂肪肝、骨质疏松;
优选地,所述的因激素紊乱导致的衰老及相关症状包括围绝经期、更年期综合征。
12.一种辅助生殖用品,其包括权利要求1所述多肽和或权利要求2所述衍生物;
优选地,所述辅助生殖用品为辅助生殖过程中卵母细胞和或受精卵的保护液。
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