CN114920814A - 一种活性多肽及其药物应用 - Google Patents

一种活性多肽及其药物应用 Download PDF

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CN114920814A
CN114920814A CN202210403779.6A CN202210403779A CN114920814A CN 114920814 A CN114920814 A CN 114920814A CN 202210403779 A CN202210403779 A CN 202210403779A CN 114920814 A CN114920814 A CN 114920814A
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姜绮霞
李晓光
李举堂
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Abstract

本申请公开一种氨基酸序列如SEQINNO.1所示的内源性多肽及其在制备抑制巨噬细胞泡沫化和抗动脉粥样硬化药物中的应用，涉及生物医药领域；该内源性活性多肽MFDP5来源人体，分子量小、亲脂性高、稳定性强、半衰期长、保守性高，具有抑制
Figure DDA0003600999790000011
泡沫化和增加AS斑块稳定性的作用，具有制备抑制巨噬细胞泡沫化和抗动脉粥样硬化药物的应用前景。

Description

一种活性多肽及其药物应用
技术领域
本申请涉及生物医药领域，特别是一种内源性多肽及其在制备抑制巨噬细胞泡沫化和抗动脉粥样硬化药物中的应用。
背景技术
动脉粥样硬化(Atherosclerosis，AS)是一种累及动脉血管壁的慢性炎症性疾病，其所致的心血管疾病(Atherosclerotic cardiovascular disease，ASCVD) 始终是全球死亡率前列的原因。在全球老龄化大背景下，AS疾病带来的社会负担陡增，防治难度凸显。ASCVD急性事件的源头是斑块不稳定性的增加，目前通过强化抗血小板治疗、降脂治疗以及血运重建等措施虽对降低急性事件的死亡率有一定帮助，但是在疾病早期稳定AS斑块的手段仍然匮乏。
胆固醇对血管壁的浸润是AS病变的开端，而慢性炎症贯穿于AS病变的全过程。现阶段基于抗炎治疗AS的临床研究显示，虽获得减少AS复合终点事件下降的证据，但心血管死亡率和全因死亡率却未见降低，而致死性感染风险显著增加；因此，全身抗炎治疗遇到巨大阻碍。
现有研究表明，巨噬细胞(Macrophages，
Figure BDA0003600999770000011
)在AS病程中发挥重要作用，其吞噬脂质致泡沫化不仅仅是细胞表型的转变，还发挥持续促炎的功能。因此，“胆固醇毒性→
Figure BDA0003600999770000012
泡沫化→慢性炎症”构成AS斑块不稳定性增加的重要证据链 (1.Chinetti-Gbaguidi G,Colin S,Staels B.Macrophage subsets in atherosclerosis.Nat Rev Cardiol.2015；12(1):10-17；2.Dawn M Fernandez,Adeeb H Rahman,Nicolas F Fernandez, AlekseyChudnovskiy,El-Ad DavidAmir,Letizia Amadori,Nayaab S Khan,Christine K Wong,Roza Shamailova,Christopher A Hill,Zichen Wang,Romain Remark,Jennifer R Li,Christian Pina,Christopher Faries,Ahmed J Awad,Noah Moss,Johan L MBjorkegren,Seunghee Kim-Schulze,Sacha Gnjatic,Avi Ma'ayan,J Mocco,PeterFaries,Miriam Merad,Chiara Giannarelli.Single-cell immune landscape of humanatherosclerotic plaques.Nat Med. 2019；25(10):1576-1588；3.Thomas F Lüscher.Understanding cardiovascular disease:macrophage function,LDL-receptortrafficking,and C-type natriuretic peptide.Eur Heart J.2020；41(9): 975-979；4.HaiderM,Al-Rashed F,Albaqsumi Z,AlobaidK,Alqabandi R,Al-Mulla F,Ahmad R.Candida albicans Induces Foaming and Inflammation in Macrophages throughFABP4:Its Implication forAtherosclerosis.Biomedicines.2021；9(11):1567).然而目前尚无有效抑制M φ泡沫化的药物。
内源性多肽是体内天然存在具有生理功能和生物学活性的小分子物质，可能通过与蛋白结合的方式在细胞内发挥作用。实验证明，大鼠脂肪组织来源的内源性多肽可以协助脂肪细胞完成胰岛素诱导的葡萄糖摄入(Berti DA,Russo LC,Castro LM,Cruz L,GozzoFC,Heimann JC,LimaFB,OliveiraAC,Andreotti S,Prada PO,HeimannAS, FerroES.Identification of intracellular peptides in rat adipose tissue:Insightsinto insulin resistance.Proteomics.2012；12(17):2668-2681)，促红细胞生成素来源的多肽能够显著改善高脂喂养小鼠的肥胖和胰岛素抵抗(Liu Y,Luo B,Shi R,Wang J,LiuZ,Liu W, Wang S,Zhang Z.Nonerythropoietic erythropoietin-derived peptidesuppresses adipogenesis, inflammation,obesity andinsulinresistance.SciRep.2015；5:15134.)。内源性多肽在制备抑制
Figure BDA0003600999770000021
泡沫化和稳定AS斑块药物中的应用尚未见报道。
发明内容
针对上述问题，本申请提供一种内源性活性多肽，该多肽可以应用于制备抑制巨噬细胞泡沫化和抗动脉粥样硬化的药物。
具体而言，本申请是通过如下技术方案实现的：
首先，本申请提供了一种氨基酸序列如SEQ ID NO.1所示的内源性多肽，申请人将其自命名为
Figure BDA0003600999770000024
泡沫化来源多肽5(Macrophage foaming derived peptide 5，MFDP5)。
该内源性活性多肽MFDP5来源人体s，分子量小、亲脂性高、稳定性强、半衰期长、保守性高，具备药物临床转化的潜力。
其次，本申请提供了上述内源性活性多肽MFDP5在制备抑制巨噬细胞泡沫化药物中的应用。
第三，本申请提供了上述内源性活性多肽MFDP5在制备抗动脉粥样硬化药物中的应用。
申请人前期利用多肽组学筛选发现MFDP5在泡沫化
Figure BDA0003600999770000023
和人颈动脉AS不稳定斑块中均呈现低表达，且MFDP5具有抑制
Figure BDA0003600999770000022
泡沫化和增加AS斑块稳定性的作用。实施例同时验证该MFDP5具有较好的抑制巨噬细胞泡沫化和抗动脉粥样硬化的药物应用。
附图说明
图1为MFDP5抑制Mφ泡沫化的细胞功能学验证结果；
其中，A为不同浓度MFDP5干预THP-1对细胞活力的影响实验结果示意图；B为MFDP5对THP-1细胞内脂质蓄积的影响实验结果示意图；C为MFDP5 抑制THP-1细胞内的脂质蓄积的镜检照片；D为MFDP5对THP-1细胞内CE/TC 比值的影响实验结果示意图；E为MFDP5对THP-1细胞内炎症因子释放的影响实验结果示意图；*P＜0.05，***P＜0.001。
图2为MFDP5稳定小鼠AS斑块的在体检测结果；
其中A为MFDP5处理后AS小鼠斑块稳定性的变化(苏丹V染色)；B为 MFDP5处理后AS小鼠斑块稳定性的变化(Masson染色)；C为MFDP5对AS小鼠血清中炎症因子(pg/ml)释放的影响统计结果；D为MFDP5处理不同时间， AS小鼠血清中TC(mg/dL)释放的变化结果示意图；E为MFDP5处理不同时间， AS小鼠血清中TG(mg/dL)释放的变化统计结果示意图；**P＜0.01，***P＜ 0.001。
图3为MFDP5的生物特性检测结果示意图；
其中，A为镜下观察化学合成FITC荧光标记的MFDP5加入THP-1后的检测结果；B为靶向质谱检测MFDP5在THP-1和泡沫化THP-1中表达检测统计结果；C为靶向质谱检测MFDP5在健康志愿者和CEA患者外周血中表达统计结果；***P＜0.001。
具体实施方式
以下实验已通过医院伦理委员会批准。
实施例1 MFDP5生物信息学分析
申请人在人颈动脉AS不稳定斑块VS.人颈动脉AS稳定斑块差异表达多肽，的交集肽中，筛选泡沫化
Figure BDA0003600999770000032
VS.
Figure BDA0003600999770000033
差异表达肽，并进一步筛查出靶目标肽
Figure BDA0003600999770000031
泡沫化来源多肽5(Macrophage foaming derivedpeptide 5，MFDP5)。
再以“质谱信号高、组间差异倍数大、组内差异小”为原则，利用Peptideranker(http://distilldeep.uc d.ie/PeptideRanker/)进行生物活性分析、采用ProtParam(https://web.expasy.org/protparam/)行成药性特点分析，结果发现MFDP5脂肪族氨基酸系数分布在97.5～156，为亲脂性氨基酸，易透过细胞膜；哺乳动物体内理论半衰期均为30h，具有稳定性高、不易被降解等可能性；分子量分布在16 68.04～2941.66，由上海科肽生物科技有限公司(公司网站： http://www.scipeptide.com/)合成，相关参数如下表1所示：
表1 MFDP5基本特征
Figure BDA0003600999770000041
实施例2 MFDP5抑制巨噬细胞泡沫化细胞学实验
以THP-1细胞(人源性单核-巨噬细胞系，购自中国科学院细胞库)为研究对象开展以下功能研究：：
1)细胞培养及分组
THP-1细胞用含20％胎牛血清的RPMI640培养液培养(购于Hyc lone公司)，于37℃、5％CO2的细胞培养箱中培养，取对数期细胞进行实验；
2)加佛波醇酯(160μmol·L－1)于培养液，72h后待悬浮细胞分化为贴壁生长的巨噬细胞后，用PBS清洗3次，换含抗氧化剂EDTA和 BHT无血清培养基培养4h，将细胞分为3组：
①对照组(5mg·L－1LDL)；
②炎症刺激组(5mg·L－1LDL+200μg·L－1LPS)；
③炎症+雷帕霉素组(5mg·L－1LDL+200μg·L－1 LPS+10μg·L－1Rapamycin)。
以上各组细胞培养24h后收获。
2)泡沫细胞鉴定
待悬浮细胞分化为贴壁生长的巨噬细胞后，用PBS清洗次，换含0.2％ BSA无血清培养基培养4h，用冷PBS清洗3次，4％多聚甲醛固定30min，油红O染色液染色20min，苏木精复染。
此外，MFD5+ox-LDL组中加入终浓度为50μg/ml的MFDP5，检测结果如图1所示。可见，50μg/mLMFDP5抑制ox-LDL对THP-1细胞的毒性作用，且呈浓度依赖性(如图1中A所示)MFDP5显著抑制THP-1细胞内的脂质蓄积，维持细胞内脂质平衡(如图1中B所示)；MFDP5抑制THP-1细胞内的脂质蓄积的镜检照片如图1中C所示；细胞内CE和TC的比值显示，加入 MFDP5后CE/TC<50％，显著抑制
Figure BDA0003600999770000051
泡沫化(如图1中D所示)；相比于对照组，MFDP5显著降低THP-1细胞上清液中炎症相关因子IL-4、IL-1α、 IL-1β和TNF-α的含量(如图1中E所示)。
本实施例中使用的研究方法和试剂为常规方法，如文献“非酒精性脂肪肝病大鼠IL-1β、IL-18、TNF-α水平的变化”(李飒林等，安徽医科大学学报，2016)；炎症应激通过激活mTOR通路诱导THP-1巨噬细胞泡沫化的实验研究(赵爽等，中国药理学通报，2016)”中所公开的方法。
实施例3 MFDP5稳定小鼠AS斑块研究实验
构建LDLR-/-AS不稳定斑块小鼠模型(LDLR-/-小鼠Gene ID:16835，购于“赛业(苏州)生物科技有限公司，https://www.cyagen.com/cn/zh-cn/，)。本实施例小鼠构建模型为常规方法，如文献“Eelke Brandsma,Niels J Kloosterhuis,Mirjam Koster,Daphne CDekker,Marion J J Gijbels,Saskia van der Velden,Melany Ríos-Morales, MartijnJ R van Faassen,Marco G Loreti,Alain de Bruin,Jingyuan Fu,Folkert Kuipers,Barbara M Bakker,Marit Westerterp,Menno P J de Winther,Marten H Hofker,Bartvan de Sluis,Debby P Y Koonen.A Proinflammatory Gut Microbiota IncreasesSystemic Inflammation andAcceleratesAtherosclerosis.Circ Res.2019；124(1):94-100.”中公开的构建方法。MFDP51mg/kg皮下微泵连续2周至体内持续作用，后安乐死处理小鼠。
安乐死前取小鼠尾静脉血，安乐死后取小鼠颈动脉AS斑块组织。对取出的AS斑块组织行苏丹V和Masson染色均发现，MFDP5处理降低AS斑块大小、增加斑块稳定性(如图2中A和B所示)。
采血利用ELISA(ELISA试剂盒购自上海源叶生物技术有限公司)实验证明MFDP5显著降低小鼠血清中炎症因子IL-4、IL-1α、IL-1β和TNF-α的释放(如图2中C所示)；检测小鼠血清TC和TG含量，MFDP5显著降低了血清TC和TG含量(如图2中D和E所示)。检测方法同实施例2。
实施例4 MFDP5的生物特性实验
本实施例对MFDP5进行全面的生物信息学分析，发现MFDP5由25个氨基酸组成，分子量2.9kDa；哺乳动物体内半衰期约30h，稳定性高；脂肪族氨基酸系数为156，亲水系数仅为1.44，脂溶性较强、容易通过分子扩散进入细胞内，如表2所示：
表2 MFDP5生信分析特点
Figure BDA0003600999770000061
化学合成FITC荧光标记的MFDP5(50μg/ml)加入
Figure BDA0003600999770000062
后1h后， MFDP5开始进入细胞，培养24h后仍可见荧光持续表达(如图3中A所示)。
利用靶向质谱技术(交由商业公司检测)检测正常
Figure BDA0003600999770000064
和泡沫化
Figure BDA0003600999770000065
中 MFDP5的含量，结果发现泡沫化
Figure BDA0003600999770000063
中MFDP5的含量显著降低(如图3 中B所示)。进一步收集行利用行颈动脉内膜剥脱术(Carotid endarterectomy， CEA；具体操作方法参见文献“曲乐丰.颈动脉内膜斑块切除术:手术技巧及围术期处理[M].人民军医出版社,2015.”所公开内容)、术前颈动脉MRI评估合并斑块内出血(Intraplaque hemorrhage，IPH；具体操作方法参见文献“DanielBos, Banafsheh Arshi,Quirijn J A van den Bouwhuijsen,M Kamran Ikram,Mariana Selwaness, Meike W Vernooij,Maryam Kavousi,Aad van derLugt.Atherosclerotic Carotid Plaque Composition and Incident Stroke andCoronary Events.J Am Coll Cardiol. 2021；77(11):1426-1435.”所公开内容)、且血清超敏C反应蛋白(high-sensitivity C-reactive protein，hsCRP；具体检测方法参见文献“Paul M Ridker,Jean G MacFadyen,Tom Thuren,Brendan M Everett,Peter Libby,Robert J Glynn,CANTOS Trial Group.Effect ofinterleukin-1βinhibition withcanakinumab on incident lung cancer in patients with atherosclerosis:exploratory results from a randomised,double-blind,placebo-controlledtrial.Lancet.2017；390(10105):1833-1842”所公开内容)≥2mg/L患者与正常志愿者外周静脉血样本各10例，靶向质谱检测发现，CEA患者外周血中MFDP5含量显著降低(如图3中C所示)。
以上实施例验证了MFDP5具有较好的抑制巨噬细胞泡沫化和抗动脉粥样硬化应用，可以应用于制备的抑制巨噬细胞泡沫化药物和抗动脉粥样硬化药物。
序列表
<110> 上海市同仁医院
<120> 一种内源性多肽及其药物应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 25
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Met Leu Leu Lys Cys Ser Ile Gln Trp Leu Leu Val Tyr Leu Leu Cys
1 5 10 15
Cys Ala Thr Ile Asp Thr Ile His Phe
20 25

Claims (3)

1.一种氨基酸序列如SEQ ID NO.1所示的内源性多肽。
2.如权利要求1所述内源性多肽在制备抑制巨噬细胞泡沫化药物中的应用。
3.如权利要求1所述内源性多肽在制备抗动脉粥样硬化药物中的应用。
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