CN108129553B - 防治端粒功能异常相关疾病的多肽及医药用途 - Google Patents
防治端粒功能异常相关疾病的多肽及医药用途 Download PDFInfo
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Abstract
发明提供一种抑制端粒损伤的多肽，命名为TELODIN，选自十二种抑制端粒功能异常的多肽中的一种，包括其各种不同变异、衍生结构。本发明多肽防治有和没有应激状态下的端粒损伤、端粒缩短，取得延长端粒的结果，增进干细胞扩增，增加和改善肺呼吸功能，增加皮肤毛囊的数量，延长应激条件下小鼠的寿命，能抑制端粒功能异常，有延缓和抗衰老、延长寿命功效，可防治因应激引起的肺和皮肤衰老相关性疾病和状态，通过抑制细胞内染色体端粒的损伤和缩短，达到延缓衰老、防止过早死亡和防治相关疾病的作用。可在制备延缓衰老和防治端粒功能异常相关疾病药物中的应用，包括因端粒损伤导致组织器官衰老、变性、纤维化、功能障碍及衰竭相关疾病的药物。
Description
技术领域
本发明属于生物技术领域，涉及防治端粒功能异常相关疾病的多肽及医药用途，具体涉及使用体外合成的多肽--即氨基酸序列，以及所述多肽在制备防治端粒功能异常相关疾病的药物中的应用，尤其涉及所述多肽通过抑制细胞内染色体端粒的损伤和缩短，达到抗衰老和防治相关疾病的医药用途。
背景技术
衰老相关的慢性疾病如肺纤维化、皮肤纤维损伤，是因为端粒DNA损伤、进而细胞衰老引起。染色体端粒损伤逐渐缩短是导致细胞衰老的公认机制。应激、如射线照射、抗生素等化学物质引起的DNA断裂、以及氧化应激，加速端粒损伤缩短，引起过早衰老，但几十年来、应激是如何引起端粒损伤缩短进而导致过早衰老及相关疾病的机制还不清楚。作为过早衰老相关的疾病，特发性肺纤维化的病因、先天性皮肤角化不良综合症的病因也都不清楚，临床上无治疗药物。
辐照应激，氧化应激和DNA损伤药物博来霉素已被证明引起肺纤维化，引起端粒缩短，但具体机制未知。有趣的是，不同应激可激活E3泛素连接酶FBW7。FBW7(F-box and WD40repeat domain-containing 7,also termed FBXW7,Sel-10,hCDC4,or hAgo)作为底物识别组分，靶向降解底物蛋白，包括c-myc，n-myc，Notch，cyclin E，c-Jun，Aurora-A和mTOR等癌蛋白的降解。在哺乳动物小鼠中，FBW7功能的缺失激活干细胞扩增；在多种人类肿瘤中FBW7有发生突变，但FBW7在细胞增殖中的抑制作用尚不完全清楚。
端粒结合蛋白TPP1是覆盖端粒DNA蛋白复合体shelterin的一个重要组分。编码TPP1的ACD基因突变参与衰老相关疾病如先天性角化不良和骨髓衰竭。端粒损伤，包括端粒缩短、端粒功能异常，引起端粒损伤反应，参与衰老过程，加速衰老，是衰老相关疾病的重要致病前体。已经报道的与端粒异常密切相关的衰老相关疾病包括慢性阻塞性肺病如肺纤维化等纤维组织增生性疾病，肝纤维化，骨髓干细胞减少、贫血及免疫功能低下，胸腺纤维化，免疫功能低下，卵巢纤维化，卵巢早衰，骨关节纤维化，骨质疏松，血管纤维化动脉硬化，心脏疾病，肾纤维化，神经退行性损伤和疾病，糖尿病，皮肤老化如角化不良,肿瘤等(Science,350:1193-8,2015；Clin Sci(Lond).120(10):427-40，2011)。例如，肺衰老是肺纤维化的重要前体，作为高致死率的特发性肺纤维化，TPP1含量降低，端粒损伤缩短，肺泡上皮干细胞复制、增殖和分化障碍。
发明内容
发明的目的是提供一种抑制端粒损伤的多肽，所述多肽选自表1中列举的十二种多肽中的一种。本发明从针对FBW7的氨基酸序列，通过人工设计、合成一系列多肽，并对多肽进行了系统筛选，发现包括十二种抑制端粒功能异常的多肽，取名为TELODIN，即telomere dysfunction inhibitor。这十二种抑制端粒功能异常的TELODIN多肽(表1)。所述十二种多肽包括其各种不同变异、衍生结构、对应结构、类似物、以及模拟结构对应结构、类似物、以及模拟结构。
表1：TELODIN多肽
本发明的第二个目的是提供所述多肽(TELODIN)在制备防治端粒功能异常药物中的应用，尤其在制备抑制和延缓因端粒损伤导致器官衰老、变性、纤维化、功能障碍及衰竭、过早死亡方面相关的药物中的应用。涉及延缓上皮组织如肺上皮、肝上皮、皮肤的变性、纤维化，延缓骨髓组织如骨髓干细胞、造血干细胞和免疫干细胞的衰老，延长器官和机体寿命、防止过早死亡等方面的应用。
所述端粒功能异常包括因端粒损伤或缩短引起的包括肺纤维化，心肌纤维化，肝纤维化如肝硬化，肾纤维化，骨髓纤维化，骨髓干细胞减少、贫血及免疫功能低下，胸腺纤维化，免疫功能低下，卵巢纤维化，卵巢早衰，骨关节纤维化，骨质疏松，血管纤维化，神经退行性损伤，糖尿病，皮肤老化如皮肤皱纹、角化不良、毛发再生障碍及白发，肿瘤，以及与年龄相关的慢性阻塞性肺病。本发明多肽通过抑制细胞内染色体端粒的损伤和缩短，达到抗衰老和防治相关疾病的治疗作用。
本发明研究显示，以上12种TELODIN多肽，均源于FBW7碳端的氨基酸序列、即687GSRNGTEETK，表明FBW7碳端的氨基酸序列具有抑制端粒损伤活性，证明任何基于FBW7碳端的氨基酸序列的结构，包括以上描述的12种TELODIN多肽，如TELODIN多肽SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21；TELODIN多肽SEQ ID No.12,TyrGlyArgLysLysArgArgGluArgArgArgArgAsnGlyThrGluGluThrLys,名称YK21a；TELODIN多肽SEQ ID No.14,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgGlyThrGluGluThrLys，名称YK21c；TELODIN多肽SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21；SEQ ID No.20,LysThrGluGluThrGlyAsnArgSerGlyArgArgArgGlnArgArgLysLysArgGlyTyr，名称DKY21；TELODIN多肽SEQ ID No.21,LysThrGluGluThrGlyAsnArgSerGlyArgArgArgGlnArgArgLysLysArgGlyTyr，名称KY21；TELODIN多肽SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)，以及在这些结构基础上的修饰、衍生的其它结构，均具有抑制端粒损伤的作用。
本发明研究揭示，每个TELODIN多肽可以有效地抑制端粒损伤，因此每个TELODIN多肽、及其相关结构，包括修饰及衍生的结构，都具有预防和治疗因端粒损伤引起的疾病，尤其是端粒损伤导致的衰老相关性疾病。以TELODIN多肽SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21为例，一次性经气管使用，提高小鼠肺呼吸功能，防止应激引起的小鼠肺呼吸功能障碍，防止肺衰老损伤和肺纤维化，延长端粒长度，增加肺干细胞数量。再以TELODIN多肽SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8为例，给与小鼠一次性器官用药，提高动物肺呼吸功能，防止应激引起的肺呼吸功能障碍，防止肺衰老损伤和肺纤维化，延长端粒长度，增加肺干细胞数量。
除具有防治应激引起的肺纤维化用途，TELODIN多肽还具有防治其它因为应激而引起的皮肤损伤、老化性疾病。以TELODIN多肽SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21为例，在小鼠背部皮肤涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)，引起真皮层干细胞数量明显增加，毛囊数量明显增加。在有X射线照射后，对照组动物发生明显皮肤增厚、皮肤纤维化，真皮层出现大量纤维组织增生，但TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)涂抹皮肤的小鼠则对X射线引起的皮肤纤维化具有了抵抗能力，完全预防了射线引起皮肤老化、纤维化。此外，皮肤涂抹TELODIN多肽SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21能抑制白发生成。
应用本发明提供的TELODIN多肽防治基础状态下和应激状态下的端粒损伤，防治了端粒缩短，取得明显的延长端粒的结果，增进了干细胞的扩增，增加和改善肺呼吸功能，增加皮肤毛囊的数量，延长应激条件下小鼠的寿命。因此，表明TELODIN多肽具有抗衰老、延缓衰老的功效，包括在抵抗肺衰老，皮肤衰老，脑衰老，心脏、骨髓、免疫肝脏等组织器官衰老等方面的用途。
应用本发明提供的TELODIN多肽防治有和没有应激状态下的端粒损伤、端粒缩短，取得延长端粒的结果，增进了干细胞的扩增，防治因应激引起的肺和皮肤衰老相关性疾病和状态。因此，表明TELODIN多肽具有防治其它因端粒损伤或缩短引起的疾病和状态，包括心肌纤维化，肝纤维化、如肝硬化，肾纤维化，骨髓纤维化，造血细胞减少，贫血，胸腺纤维化，免疫功能低下，卵巢纤维化，卵巢早衰，骨关节纤维化，骨质疏松，血管纤维化，神经退行性损伤。
附图说明
图1为多肽TELODIN具有抑制端粒损伤和预防肺纤维化的作用；其中图1A和1B为不同多肽对辐照条件下HeLa细胞端粒DNA损伤的情况。结果显示；在博莱霉素处理条件下，TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)明显降低了基础水平的端粒损伤，抑制了放射线引起的端粒损伤。图1C为小鼠实验经呼吸道给药时间方案。结果于图1D，1E和1F显示，在博莱霉素处理条件下，TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)及其对照肽(SEQ ID No.2，名称YK21h)对小鼠呼吸功能的改善作用和防止损伤作用；图1G和1H为上述处理条件下，TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)对肺纤维化的预防作用；图1I为上述处理条件下，TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)对TPP1和SPC的mRNA表达的改善作用；图1J为上述处理条件下，TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)对肺二型上皮细胞的端粒长度的延长作用；图1K为辐照条件下，TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)对肺组织端粒DNA损伤的防护情况。我们发现，最短的8个氨基酸的TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)具有抑制端粒损伤的活性，改善端粒功能(图1L)。
图2为8个氨基酸的TELODIN多肽对肺纤维化的保护作用；图2A,2B和2C显示TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)与对照多肽(SEQ IDNo.24，名称GE8)比较，改善正常呼吸功能，抑制博莱霉素引起小鼠呼吸功能障碍；图2D为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)在博来霉素处理条件下调节FBW7，TPP1和α-SMA的表达情况；图2E和2F为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)对肺二型上皮细胞端粒的长度的延长作用及增加肺干细胞的比例；图2G为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)预防肺纤维化的作用；图2H为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)调节NG2，T1α，s100a4，α-SMA和col6a的mRNA表达水平的功能；图2I，2J和2K为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8))对FBW7过表达引起小鼠的呼吸功能障碍的防治作用；图2L为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)对FBW7，TPP1，SPC，-SMA的mRNA表达的作用；图2M和2N为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)对FBW7抑制肺干细胞端粒的长度及干细胞的比例的防治作用；图2O和2P为TELODIN多肽(SEQ ID No.25,SerArgAsnGlyThrGluGluThr，名称ST8)对小鼠肺纤维化的防治作用。
图3显示，在小鼠北部皮肤涂抹应用TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)，每天一次、每次1mg/kg，一周时间与对照组比较，明显增加了小鼠的体重(图3A，n＝12)。检查组织学结构发现，皮肤涂抹应用TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)明显增加了真皮层干细胞和毛囊的数量(图3B-D，n＝12)。检测环境应激反应发现，对小鼠每天X-射线(4Gy)照射，一周后的小鼠出现皮肤增厚，真皮层出现明显的纤维组织增生，但是，对于小鼠X射线照射4小时前在背部皮肤涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)，则没有出现皮肤增厚、以及纤维化改变(图3B，D，E)。每日X-射线(4Gy)引起对照小鼠体重明显下降，但背部皮肤涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)小鼠的体重下降得到明显的改善(图3F)。每日X-射线(4Gy)引起对照小鼠体过早死亡，但提前4小时于小鼠背部皮肤涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)则明显延缓了小鼠死亡，延长了在严重应激状态下的存活寿命(图3G)。涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys,名称DYK21)于一位自愿者白发处每天一次，数周后白发发生减少(图3H)。
具体实施方式
下面将结合附图和实施例对本发明进行详细描述。但是本领域技术人员将会理解，下属实施例仅用于说明本发明，而不应试为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行，所用试剂或仪器未注明生成厂商者，均为可以通过市购获得的常规产品。
实施例1应用TELODIN多肽抑制端粒损伤、慢性阻塞性肺病及肺纤维化
实验对象：人宫颈癌细胞Hela，3-6月龄野生型小鼠18只
实验方法：Hela细胞利用多个多肽(表2，SEQ ID No.1-21)处理4小时后，分别对细胞进行0Gy和5Gy处理，1小时后取细胞利用免疫荧光结合原位杂交检测端粒DNA损伤；18只野生型小鼠分成6组，每组3只，小鼠处理如下，气管灌注TELODIN多肽(SEQ ID No.1，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)或对照肽(SEQ ID No.2，TyrGlyArgLysLysArgArgGluArgArgArgGlyGluArgAsnGlyThrGluGluThrLys,名称YK21h，1mg/kg体重)，4小时后气管灌注博来霉素(3mg/kg体重)，另有两组小鼠在灌注博来霉素24小时再灌注一次多肽，21天后对小鼠进行气管插管检测呼吸功能；提取肺组织RNA，实时定量PCR检测TPP1和SPC的mRNA表达；肺组织石蜡包埋切片，Masson和H&E染色，利用免疫荧光检测α-SMA表达情况；取10mg肺组织检测羟脯氨酸含量；利用免疫荧光结合FISH检测二型细胞的端粒长度(SPC+端粒探针)以及肺组织中的端粒DNA损伤(53BP1+端粒探针)。
表2为检测的FBW7多肽序列，标记为TELODIN的多肽具有抑制端粒损伤活性，是本发明的核心结构，包括其各种不同变异、衍生结构。
表2
结果显示：TELODIN多肽(SEQ ID No.1 TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称YK21)显著降低基础水平的端粒DNA损伤，并完全抑制辐照引起的端粒DNA损伤(图1A-B)。此多肽是序列依赖性的。该多肽显著增加小鼠呼吸功能(图1D-F)。此外，TELODIN阻断博来霉素诱导的小鼠肺纤维化表型(图1G-H)，增加TPP1和SPC的表达(图1I)，延长二型上皮细胞的端粒长度(图1J)。在细胞中加入TELODIN多肽(SEQID No.19，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称DYK21)和TELODIN多肽(SEQ ID No.20，LysThrGluGluThrGlyAsnArgSerGlyArgArgArgGlnArgArgLysLysArgGlyTyr，图中名称DKY21)后发现，全右旋氨基酸的TELODIN多肽抑制X-射线照射引起的端粒DNA损伤(图1K，表3)。在保护端粒DNA损伤方面，8个氨基酸的TELODIN多肽(SEQ ID No.25，SerArgAsnGlyThrGluGluThr，名称ST8)显著降低X-射线照射引起的端粒DNA损伤(图1L)。
表3
实施例2应用TELODIN多肽抑制端粒损伤、慢性阻塞性肺病及肺纤维化
实验对象：3-6月龄野生型小鼠24只
实验方法：12只野生型小鼠分成4组，每组3只，小鼠处理如下，气管灌注TELODIN多肽(SEQ ID No.25，SerArgAsnGlyThrGluGluThr，名称ST8)或对照肽(SEQ ID No.24，GlySerArgAsnGlyThrGluGlu，名称GE8，1mg/kg体重)，4小时后气管灌注博来霉素(3mg/kg体重)，21天后对小鼠进行气管插管检测呼吸功能；利用流式分选二型细胞，并统计二型细胞百分比；提取肺组织RNA，实时定量PCR检测NG2，T1α，s100a4，α-SMA和Col6a的mRNA表达；提取肺组织蛋白质，免疫印迹检测FBW7，TPP1，α-SMA和内参GAPDH的表达；肺组织石蜡包埋切片，Masson和H&E染色，利用免疫荧光检测α-SMA表达情况；取10mg肺组织检测羟脯氨酸含量；利用免疫荧光结合FISH检测二型细胞的端粒长度(SPC+端粒探针)。另12只小鼠分成4组，每组3只，处理如下，气管灌注TELODIN多肽(SEQ ID No.25，SerArgAsnGlyThrGluGluThr，名称ST8)或对照肽(SEQ ID No.24，GlySerArgAsnGlyThrGluGlu，名称GE8，1mg/kg体重)，4小时后分别气管灌注control和FBW7慢病毒，每隔4天灌注一次，共计灌注4次，在第4次灌注后4天对小鼠进行气管插管检测呼吸功能；提取肺组织RNA，实时定量PCR检测α-SMA，Col6a和MMP3的mRNA表达；提取肺组织蛋白质，免疫印迹检测FBW7，TPP1，SPC，α-SMA和内参GAPDH的表达；肺组织石蜡包埋切片，Masson和H&E染色，利用免疫荧光检测α-SMA表达情况；利用免疫荧光统计肺二型上皮细胞的百分比(SPC阳性细胞)；利用免疫荧光结合FISH检测二型细胞的端粒长度(SPC+端粒探针)。
结果显示：更短的TELODIN多肽(8个氨基酸，表3)同样抑制辐照引起的端粒DNA损伤。短多肽依然可以保护博来霉素引起的小鼠呼吸功能障碍(图2A-C)，抑制FBW7，保护TPP1(图2D)，延长端粒，增加肺二型上皮细胞的比例(图2E-F)。与此一致的是，TELODIN多肽(SEQID No.25，SerArgAsnGlyThrGluGluThr，名称ST8)抑制博来霉素引起的小鼠肺纤维化(图2G-H)。在FBW7过量表达的小鼠肺组织中也发现TELODIN多肽(SEQ ID No.25，SerArgAsnGlyThrGluGluThr，名称GE8)发挥保护作用，改善FBW7过量表达引起小鼠呼吸障碍，TPP1表达降低，端粒缩短，二型上皮细胞比例降低和肺纤维化(图2I-P)。
实施例3应用TELODIN多肽防止放射损伤引起皮肤衰老老化、体重丢失及过早死亡
实验对象：2-4月龄野生型小鼠48只
实验方法：取48只野生型小鼠随机分为4组，每组12只。先将全部小鼠背部脱毛面积约2×2cm。各组小鼠处理如下：两组小鼠不进行X-射线照射处理，每天分别涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称DYK21)或对照多肽(SEQ ID No.28，AlaCysThrGlySerThrGlnHisGlnCysGlyGlyGlyGlySerArgAsnGlyThrGluGluThr，图中名称AT22)，连续7天。另两组小鼠每天在分别涂抹含有每天分别涂抹TELODIN多肽(SEQ ID No.19,TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称DYK21)或对照多肽(SEQ ID No.28，AlaCysThrGlySerThrGlnHisGlnCysGlyGlyGlyGlySerArgAsnGlyThrGluGluThr，图中名称AT22)，四小时后进行4Gy的X-射线照射，连续7天。每天拍照并称重。第8天处死小鼠，取皮肤组织。
结果显示：在连续7天的X-射线照射后，各组均有小鼠死亡，但涂抹TELODIN多肽(SEQ ID No.19，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称DYK21)小鼠体重高于对照组(图3A)，毛囊数量明显增多(图3B-D，箭头)，X-射线照射引起小鼠皮肤损伤纤维组织增生(图3B，D，星标处)收到明显抑制，(图3B，D，E)，小鼠背部皮肤涂抹TELODIN多肽(SEQ ID No.19，TyrGlyArgLysLysArgArgGluArgArgArgGlySerArgAsnGlyThrGluGluThrLys，名称DYK21)较比对照组的因X射线引起的体重下降受到抑制(图3F)、急性死亡受到一定缓解，部分小鼠的寿命得到延长(图3G)。对人毛发灰白头部皮肤涂抹TELODIN多肽可具有抑制白发的作用(图3H)。
序列表
<110> 杭州端丽生物技术有限公司
<120> 防治端粒功能异常相关疾病的多肽及医药用途
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Claims (3)
1.一种抑制端粒损伤的多肽，其特征在于，选自SEQ ID No.1、SEQ ID No.19、SEQ IDNo.20、SEQ ID No.25中的一种。
2.根据权利要求1所述的一种抑制端粒损伤的多肽，其特征在于，其中SEQ ID No.1所述多肽命名为YK21，分子量为2619.96； SEQ ID No.19所述多肽命名为DYK21，分子量为2619.94；SEQ ID No.20所述多肽命名为DKY21，分子量为2619.96； SEQ ID No.25所述多肽命名为ST8，分子量为892.88。
3.权利要求1所述的抑制端粒损伤的多肽在制备防治端粒功能异常药物中的应用，其特征在于，所述多肽在制备抑制辐射引起的端粒DNA损伤；阻断辐射或博来霉素诱导的小鼠肺纤维化表型；延长肺上皮细胞的端粒长度；抑制辐射引起的小鼠皮肤损伤、纤维组织增生；抑制辐射引起的毛囊数量减少，增加毛囊数量；抑制辐射引起的体重下降，缓解急性死亡，延长小鼠寿命；抑制白发生成的药物中的应用。
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| PCT/CN2018/124178 WO2019134574A1 (zh) | 2018-01-05 | 2018-12-27 | 防治端粒功能异常相关疾病的多肽及医药用途 |
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| CN113633754B (zh) * | 2021-09-28 | 2022-08-30 | 上海揽微赛尔生物科技有限公司 | 卵巢干细胞在制备卵巢抗衰的药物中的用途 |
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