CN112125953B - 一种抗血小板聚集的多肽 - Google Patents

一种抗血小板聚集的多肽 Download PDF

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CN112125953B
CN112125953B CN202010716442.1A CN202010716442A CN112125953B CN 112125953 B CN112125953 B CN 112125953B CN 202010716442 A CN202010716442 A CN 202010716442A CN 112125953 B CN112125953 B CN 112125953B
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叶雨佳
孟照辉
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First Affiliated Hospital of Kunming Medical University
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Abstract

本发明公开一种抗血小板聚集的多肽6X，该多肽为由10个氨基酸组成的多肽6X，具有SEQ ID NO:1的多肽的序列，分子量为1103.19Da，序列为Thr‑Asn‑Leu‑Thr‑Ser‑Arg‑Asn‑Leu‑Gly‑Gln，该多肽不限定于抑制FcγRIIA特异性激活剂anti‑CD9诱导的血小板聚集，可用于探索其与其它血小板激活剂(胶原、花生四烯酸、ADP、肾上腺素、瑞斯托霉素等)对血小板的作用及相关功能的影响，还可以用于监测现有的抗血小板治疗。

Description

一种抗血小板聚集的多肽
技术领域
本发明涉及医药生物技术领域，具体涉及一种抗血小板聚集的多肽6X。
背景技术
肝素诱导的血小板减少症(Heparin-Induced Thrombocytopenia，HIT)是肝素和血小板第4因子(Platelet factor 4,PF4)结合形成的抗体引起的的危及生命的罕见药物不良反应(发生率约＜0.1％-7.0％)[1]。30％-50％HIT患者有较高的血栓形成风险，而血栓形成是致死的主要原因[2]。虽然引入了新的抗凝药物，但是 HIT的发生率并没有降低，主因在手术或重症抢救期间，没有药物可以代替肝素用于急性深静脉血栓形成、动脉血栓形成或体外循环的即时治疗[3]。高度怀疑或诊断为HIT的患者应立即停用肝素，并应及时接受直接凝血酶抑制剂等抗凝治疗[4]。然而，这些替代药物不仅带来了出血风险，而且也不能有效抑制HIT患者的急性血栓形成[5]。因此研发有效预防HIT，抑制血栓形成并降低出血风险的新型药物具有重要的临床价值。
HIT抗体引起的血小板活化是免疫性血小板减少及血栓形成的主要原因。 HIT抗体是由血小板分泌的PF4与肝素分子1：1结合形成的HIT免疫复合物刺激免疫细胞产生应答而释放的IgG抗体[6]。临床上，部分使用肝素防治血栓的患者的血液循环中会出现HIT抗体，由HIT抗体介导发生的免疫反应会致血小板减少甚至发展为危及生命的血栓栓塞。HIT抗体活化血小板可触发细胞内脱颗粒(Ca2+动员，ATP释放)、细胞表面P-选择素水平上调、磷脂酰丝氨酸暴露、血小板与凝血因子X结合能力增强以及整合素αIIbβ3依赖性的血小板聚集[1]。HIT抗体介导的血小板活化一方面使血小板被脾巨噬细胞吞噬，致外周血小板减少；另一方面HIT抗体还可与FcγRI受体结合并刺激单核细胞释放组织因子及凝血酶，凝血酶与FcγRIIA共同促进血小板活化、聚集并最终导致血栓形成[7]。除血浆中的HIT抗体外，患者自身合并高凝状态、血管损伤或血流动力学异常等，也是导致血栓形成的因素。
血小板FcγRIIA是HIT抗体的主要受体。FcγRIIA是免疫球蛋白超家族中的一个重要的成员，是与含IgG的免疫复合物结合的低亲和力受体，其不表达于小鼠体内[8]。FcγRIIA分子量约为40kDa，属I型跨膜糖蛋白，其胞外段具有2个Ig样结构域，跨膜区只有一个，胞内段包含两个保守的免疫受体酪氨酸活化基序：Yxx(I/L)[9]。虽然血小板是体内FcγRIIA最丰富的来源，但FcγRIIA还在中性粒细胞、巨噬细胞等白细胞中表达，FcγRIIA在维持机体免疫及免疫耐受、血栓形成中起重要的调节作用[10]。HIT抗体及多种激活剂 (例如：anti-CD9等)与血小板膜FcγRIIA结合并活化血小板，导致血小板清除、聚集及血栓形成。研究报道也指出，FcγRIIA对整合素αIIbβ3“由外向内”信号转导同样发挥重要的协同促进作用，而整合素αIIbβ3与配体结合后也可促进FcγRIIA介导的血小板活化信号转导[11]。靶向抑制FcγRIIA介导的信号通路分子活化，能有效抑制血小板活化及血栓形成，有望成为治疗HIT 的新靶点[12,13]。
本发明涉及一个由10个氨基酸组成的多肽6X，通过体外人血血小板聚集实验来测定其对血小板聚集活性的作用。实验证明，该多肽对FcγRIIA特异性激活剂anti-CD9诱导的血小板聚集有显著的抑制作用。本发明所涉及的新的多肽6X序列，迄今尚未见到相关报道。
参考文献：
1 Arepally G.M.,Heparin-induced thrombocytopenia,Blood,2017,129(21):2864-2872.
2 Greinacher A.；Farner B.；Kroll H.；Kohlmann T.；Warkentin T.E.,EichlerP.,Clinical features of heparin-induced thrombocytopenia including riskfactors for thrombosis.A retrospective analysis of 408patients,ThrombHaemost, 2005,94(1):132-5.
3 Salter BS；Weiner MM；Trinh MA；Heller J；Evans AS；Adams DH,Fischer GW,Heparin-Induced Thrombocytopenia:A Comprehensive Clinical Review,Journal ofthe American Colege of Cardiology,2016,67(21):2519-32.
4 Cuker A.；Arepally G.M.；Chong B.H.；Cines D.B.；Greinacher A.；GruelY.；Linkins L.A.；Rodner S.B.；Selleng S.；Warkentin T.E.；Wex A.；Mustafa R.A.；Morgan R.L.,Santesso N.,American Society of Hematology 2018guidelines formanagement of venous thromboembolism:heparin-induced thrombocytopenia,BloodAdv,2018,2(22):3360-3392.
5 Greinacher A.,Warkentin T.E.,The direct thrombin inhibitor hirudin,Thromb Haemost,2008,99(5):819-29.
6 Nguyen T.H.；Xu Y.；Brandt S.；Mandelkow M.；Raschke R.；Strobel U.；Delcea M.；Zhou W.；Liu J.,Greinacher A., Characterization of the interactionbetween platelet factor 4and homogeneous synthetic low molecular weightheparins,J Thromb Haemost,2020,18(2):390-398.
7 Tutwiler V；Madeeva D；Ahn H.S；Andrianova I；Hayes V；Zheng X.L.；CinesD.B.；McKenzie S.B.；Poncz M,Rauova L,Platelet transactivation by monocytespromotes thrombosis in heparin-induced thrombocytopenia,Blood,2016, 127(4):464-72.
8 Lee RH,Bergmeier W,Platelet immunoreceptor tyrosine-basedactivation motif(ITAM)and hemITAM signaling and vascular integrity ininflammation and development,Journal of thrombosisand haemostasis:JTH,2016,14(4):645-54.
9 Arman M,Krauel K,Human platelet IgG Fc receptor FcγRIIA inimmunity and thrombosis,Journal of thrombosis and haemostasis:JTH,2015,13(6):893-908.
10 Castro-Dopico T.,Clatworthy M.R.,IgG and FcγReceptors inIntestinal Immunity and Inflammation,Front Immunol,2019, 10:805.
11 Zhi H.；Rauova L.；Hayes V.；Gao C.；Boylan B.；Newman D.K.；McKenzieS.E.；Cooley B.C.；Poncz M.,Newman P.J., Cooperative integrin/ITAM signaling inplatelets enhances thrombus formation in vitro and in vivo,Blood,2013, 121(10):1858-67.
12 Goldmann L.；Duan R.；Kragh T.；Wittmann G.；Weber C.；Lorenz R.；vonHundelshausen P.；Spannagl M.,Siess W.,Oral Bruton tyrosine kinase inhibitorsblock activation of the platelet Fc receptor CD32a(FcγRIIA):a new option inHIT？, Blood Adv,2019,3(23):4021-4033.
13 Busygina K.；Jamasbi J.；Seiler T.；Deckmyn H.；Weber C.；Brandl R.；Lorenz R.,Siess W.,Oral Bruton tyrosine kinase inhibitors selectively blockatherosclerotic plaque-triggered thrombus formation in humans,Blood,2018,131(24):2605-2616.
发明内容
本发明的目的是提供了一种抗血小板聚集的多肽6X，该多肽对FcγRIIA 特异性激活剂anti-CD9诱导的人血小板聚集具有抑制作用。
实现本发明上述目的所采取的技术方案为：一种抗血小板聚集的多肽6X，该多肽为由10个氨基酸组成的多肽6X，具有SEQ ID NO:1的多肽的序列，分子量为1103.19Da，序列为Thr-Asn-Leu-Thr-Ser-Arg-Asn-Leu-Gly-Gln，合成多肽后，经高效液相色谱法及质谱法技术验证，表明合成完整的氨基酸序列(图1、图2)。
优选的，所述的抗血小板聚集的多肽6X在制备对血小板聚集有抑制作用的制剂中的应用。
优选的，所述的抗血小板聚集的多肽6X在制备对血小板聚集以及治疗心血管疾病药物中的应用。
优选的，所述的抗血小板聚集的多肽6X在制备对血小板聚集以及治疗治疗肝素诱导的血小板减少症药物中的应用。
优选的，所述的抗血小板聚集的多肽6X在制备对血小板聚集以及治疗心血管疾病药物中的应用，该多肽为活性成分，并且含有一种或者多种药学上可接受的载体。
优选的，所述的抗血小板聚集的多肽6X在制备对血小板聚集以及治疗治疗肝素诱导的血小板减少症药物中的应用，该多肽为活性成分，并且含有一种或者多种药学上可接受的载体。
本发明所提供的多肽，经测试具有显著抑制FcγRIIA介导的血小板聚集活性，且呈现剂量依赖关系(图3、图4)。该多肽不限定于抑制FcγRIIA特异性激活剂anti-CD9诱导的血小板聚集，可用于探索其与其它血小板激活剂(胶原、花生四烯酸、ADP、肾上腺素、瑞斯托霉素等)对血小板的作用及相关功能的影响，还可以用于监测现有的抗血小板治疗。
本发明所提供的多肽的生物学特性能预见其许多应用。
本发明可涉及用于制备抗血小板聚集及治疗心血管疾病药物中的应用。
本发明可涉及用于血栓性疾病：评估血小板聚集功能；同时，因其抑制FcγRIIA介导血小板聚集作用，可用于探索抗HIT治疗的药物研发。
附图说明
图1为本发明所提供的多肽的高效液相色谱纯化图：峰值C即为6X。
图2为峰值C(6X)的二级质谱图。
图3为6X对anti-CD9诱导的血小板聚集的影响的曲线图。
图4为6X对anti-CD9诱导的血小板聚集的影响的柱状图。
具体实施方式
下面结合附图以及具体的实施例对本发明的具体实施方式进行更加详细的说明。
实施例1：6X体外抑制anti-CD9诱导的人血小板聚集
通过光学比浊法检测评价6X对anti-CD9诱导的血小板聚集的影响。健康志愿者签署献血知情同意书并给与一定的营养补助。采集静脉全血，经昆明市血液中心分离出单采血小板，于昆明医科大学附一院血液科收集单采血小板。实施步骤如下：
(1)DMSO溶解6X，调整6X浓度为25mM；在对照实验组中加入等体积的DMSO。
(2)洗涤血小板：取1mL 25℃恒温震荡储存的人单采血小板于1.5mL离心管中，加入终浓度为5mM的EDTA及0.1U/mL的Apyrase(生理盐水配制，防止离心过程中血小板聚集)，400g室温下离心10分钟；离心后的人单采血小板弃上清，在细胞沉淀中加入1mLTyrode’sBuffer B(137mM NaCl,27mM KCl,1 mM MgCl2,0.42mM NaH2PO4,5.5mM Glucose,5.55mMHEPES,0.25％Bovine Serum Albumin,pH 6.5)，5mM EDTA，0.1U Apyrase轻吹匀，400g室温下离心 10分钟；用Tyrode’s Buffer A(137mM NaCl,27mM KCl,1mM MgCl2,0.42mMNaH2PO4,5.5mM Glucose,5.55mM HEPES,0.25％Bovine Serum Albumin,pH 7.4)重悬离心后的血小板，将血小板计数调整为150-250x 109/L。70rpm,25℃震荡储存，洗涤后的血小板在1小时内使用。
(3)血小板聚集：吸取400μL洗涤血小板重悬液37℃下预热5min后在上述血小板重悬液中加入不同浓度的6X(200μM，500μM)37℃孵育20min。打开血小板聚集仪，按要求设置好参数，在孵育好的富血小板血浆中放入磁力棒，将带有磁力搅拌棒的血小板反应杯插入机器的检测孔中，将其置于血小板聚集仪测试区调零后加入anti-CD9，在37℃，1200rpm条件下观察6X对anti-CD9 引起的血小板聚集的影响，共观察5-10min。根据血小板聚集率记录血小板聚集曲线图和绘制相应的柱状图。实验数据用GraphPad Prism 8.0软件进行统计学分析。利用Student’s t test统计学方法进行组与组之间的比较。p<0.05则认为差异具有统计学意义。
如图3所示：人洗涤血小板(200x 109/L)在37℃下与不同浓度6X(200μM， 500μM)或DMSO(Vehicle)孵育20分钟，加入anti-CD9(1.25μg/mL)活化血小板，使用血小板聚集仪，描绘血小板聚集曲线。图3中呈现的是聚集实验中具有代表性的血小板聚集率曲线。图3横坐标为聚集曲线描绘的时间，纵坐标为血小板聚集仪描绘的血小板实时聚集率。聚集实验开始时，血小板聚集率为0％，随即加入anti-CD9，在实验进行到第2-5min时阳性对照组(Vehicle)、不同浓度的6X实验组(200μM，500μM)的血小板开始聚集。在聚集实验进行到第8分钟左右时，Vehicle组聚集率达峰值约为80％；在聚集曲线记录的第10 分钟，200Μm 6X实验组聚集率约为60％，250μM 6X实验组聚集率约为15％。说明书附图4所示：Vehicle和不同浓度的6X(200μM，500μM)组的血小板聚集峰值的比较的柱状图。Vehicle和不同浓度的6X(200μM，500μM)每组重复实验六次，血小板聚集峰值以均数±标准误表示，图中*代表差异有统计学意义，其中**，****分别代表与Vehicle组比较p＜0.01，p≤0.0001。
从以上结果可以看出，在上述有效剂量范围内，本发明提供的多肽6X对 FcγRIIA特异性激活剂anti-CD9诱导人血小板聚集有显著的抑制作用，且呈现剂量依赖关系。
本发明的保护范围不仅仅局限于上述实施例，上述实施例只是为了帮助解释和说明本发明，而不是对本发明的保护范围进行限制，只要设计与本发明的设计相同或者是只要是等同替换的都落在本发明所要求保护的范围之内。
SEQUENCE LISTING
<110> 昆明医科大学第一附属医院
<120> 一种抗血小板聚集的多肽
<140>
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 10
<212> PRT
<213> 人工序列
<400> 1
Thr-Asn-Leu-Thr-Ser-Arg-Asn-Leu-Gly-Gln
1 5 10

Claims (5)

1.一种抗血小板聚集的多肽6X，其特征在于：该多肽为由10个氨基酸组成的多肽6X，具有SEQ ID NO:1的多肽的序列，分子量为1103.19Da，序列为Thr-Asn-Leu-Thr-Ser-Arg-Asn-Leu-Gly-Gln。
2.一种权利要求1所述的抗血小板聚集的多肽6X在制备对anti-CD9诱导的血小板聚集有抑制作用的制剂中的应用。
3.一种权利要求1所述的抗血小板聚集的多肽6X在制备对FcγRIIA特异性激活剂anti-CD9诱导的血小板聚集有抑制作用的药物中的应用。
4.按权利要求2的应用，其特征在于：该多肽为活性成分，并且含有一种或者多种药学上可接受的载体。
5.按权利要求3的应用，其特征在于：该多肽为活性成分，并且含有一种或者多种药学上可接受的载体。
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