CN112007145A - 血浆铜蓝蛋白在治疗多发性硬化症中的新用途 - Google Patents
血浆铜蓝蛋白在治疗多发性硬化症中的新用途 Download PDFInfo
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Abstract
本发明公开了血浆铜蓝蛋白在治疗多发性硬化症中的新用途，涉及多发性硬化症治疗领域。本发明公开血浆铜蓝蛋白在制备用于治疗多发性硬化症药物中的应用。本发明的研究显示，血浆铜蓝蛋白对于实验性变态反应性脑脊髓炎(EAE)具有明显的治疗和改善作用，这预示血浆铜蓝蛋白具有治疗多发性硬化症的前景，本发明为多发性硬化症的治疗提供了新的药物选择和思路。
Description
技术领域
本发明涉及多发性硬化症治疗领域，具体而言，涉及血浆铜蓝蛋白在治疗多发性硬化症中的新用途。
背景技术
多发性硬化症(MS)，一种常见的中枢神经系统白质脱髓鞘病变自身免疫疾病，并具有高发病率、慢性病症和青壮年易患等特点。主要临床特征为肢体局部无力麻木、有刺痛感；视力丧失或视物模糊；共济失调等。潜在的致病因素包括遗传与环境等因素，例如受病毒慢性感染刺激而引发的自身免疫反应等。然而，明确的发病机制至今未知，且尚无特殊疗法。从1995年用β干扰素治疗MS至今，治疗药物仅针对抗炎和免疫抑制而研发。然而，此类药物只能缓解患者病情，达不到根治作用，且部分药物具有很大副作用，给患者及家人带来沉重的经济负担和精神压力。因此，研究多发性硬化症的发病机制并以此为理论依据寻找更有效的治疗靶点和药物具有非常重要临床意义。
鉴于此，特提出本发明。
发明内容
本发明的目的在于提供血浆铜蓝蛋白在治疗多发性硬化症中的新用途。本发明的研究显示，血浆铜蓝蛋白对于实验性变态反应性脑脊髓炎(EAE)具有明显的治疗和改善作用，这预示血浆铜蓝蛋白具有治疗多发性硬化症的前景，本发明为多发性硬化症的治疗提供了新的药物选择和思路。
本发明是这样实现的：
实验性变态反应性脑脊髓炎(EAE)小鼠是较为理想的多发性硬化症动物模型，该小鼠模型通过利用髓鞘少突胶质细胞糖蛋白(MOG)诱导T细胞增殖分化，发生自发性免疫反应，攻击髓鞘。以特异性致敏CD4+T细胞介导的中枢神经系统炎症浸润和神经元脱髓鞘为主要特征。EAE小鼠除了临床表现和MS患者极为相似，均是运动神经受损，病理过程也具有共同点，通常表现为复发型和复发-缓解型。国内外学者利用EAE动物模型，阐述MS的发病机制和病理过程，从而为疾病预防、治疗方案提供有效的理论依据。
血浆铜蓝蛋白(ceruloplasmin,Cp)是一种复杂的多组分氧化酶，在哺乳动物体内，ferroportin(Fpn)将Fe2+运输出细胞，由Cp氧化为Fe3+，结合transferrin(Tf)运输至血液中，对铁代谢过程有重要作用。这一过程能降低体内沉积的铁，以及Fenton反应产生的氧化自由基。铁离子螯合剂能抑制铁死亡发生，但血浆铜蓝蛋白是否也是通过抑制铁死亡，从而改善EAE小鼠炎症，目前并没有相关报道。
本发明以EAE小鼠作为对象，通过研究首次发现，血浆铜蓝蛋白对于EAE小鼠的症状具有明显的治疗改善作用，例如包括改善EAE小鼠的临床评分、改善EAE小鼠的脱髓鞘现象、减少EAE小鼠的神经元死亡、降低EAE小鼠的体内脂质氧化物含量、减少EAE小鼠的炎症细胞或炎症因子浸润等；上述结果充分说明，血浆铜蓝蛋白对于EAE小鼠的变态反应性脑脊髓炎具有治疗和改善作用；同时也指示，血浆铜蓝蛋白可用于治疗多发性硬化症。本发明为多发性硬化症的治疗提供了新的药物选择和思路。
基于上述研究发现，一方面，本发明提供血浆铜蓝蛋白在制备用于治疗多发性硬化症药物中的应用。
在可选的实施方式中，所述血浆铜蓝蛋白的氨基酸序列如SEQ ID NO.1所示或与其具有至少95％的同源性。
在本发明的实施例中，所用血浆铜蓝蛋白的氨基酸序列如SEQ ID NO.1所示，通过实施例的实验数据已说明该血浆铜蓝蛋白对于治疗改善EAE小鼠的炎症症状具有作用，可用于治疗多发性硬化症。但需要说明的是，在其他的实施例中，本领域技术人员可以采用与SEQ ID NO.1具有至少95％、96％、97％、98％或99％同源性的血浆铜蓝蛋白作为主要活性成分，用于治疗多发性硬化症，这也是属于本发明的保护范围。
在可选的实施方式中，所述血浆铜蓝蛋白的种属来源为哺乳动物。
血浆铜蓝蛋白在哺乳动物体内具有相同的作用过程，因此，任何哺乳动物来源的浆铜蓝蛋白都具有治疗多发性硬化症的作用，这些不同种属来源的血浆铜蓝蛋白在氨基酸序列可能存在一定程度的差异，但并不影响在其他哺乳动物体内发挥治疗作用。基于此，使用任何哺乳动物来源的血浆铜蓝蛋白作为治疗多发性硬化症主要活性成分，都是属于本发明的保护范围。
在可选的实施方式中，所述哺乳动物包括但不限于人、小鼠、大鼠、马、牛、猪、狗、猴、猿和羊。
另一方面，本发明提供血浆铜蓝蛋白在制备具有如下(a)-(d)中任一项用途的药物中的应用：
(a)：用于改善多发性硬化症患者脱髓鞘现象；
(b)：用于减少发性硬化症患者神经元死亡；
(c)：用于降低多发性硬化症患者体内脂质氧化物含量；
(d)：用于减少多发性硬化症患者炎症细胞或炎症因子浸润。
本发明实施例的研究发现，EAE小鼠给予血浆铜蓝蛋白后，能改善EAE小鼠的脱髓鞘现象、减少EAE小鼠的神经元死亡、降低EAE小鼠的体内脂质氧化物含量、减少EAE小鼠的炎症细胞或炎症因子浸润等；上述结果充分说明，血浆铜蓝蛋白对于EAE小鼠的变态反应性脑脊髓炎具有治疗和改善作用，具有上述(a)-(b)中任一项所述的新用途。
在可选的实施方式中，所述血浆铜蓝蛋白的氨基酸序列如SEQ ID NO.1所示(来自人)或与其具有至少95％的同源性。
SEQ ID NO.1：
MKILILGIFLFLCSTPAWAKEKHYYIGIIETTWDYASDHGEKKLISVDTEHSNIYLQNGPDRIGRLYKKALYLQYTDETFRTTIEKPVWLGFLGPIIKAETGDKVYVHLKNLASRPYTFHSHGITYYKEHEGAIYPDNTTDFQRADDKVYPGEQYTYMLLATEEQSPGEGDGNCVTRIYHSHIDAPKDIASGLIGPLIICKKDSLDKEKEKHIDREFVVMFSVVDENFSWYLEDNIKTYCSEPEKVDKDNEDFQESNRMYSVNGYTFGSLPGLSMCAEDRVKWYLFGMGNEVDVHAAFFHGQALTNKNYRIDTINLFPATLFDAYMVAQNPGEWMLSCQNLNHLKAGLQAFFQVQECNKSSSKDNIRGKHVRHYYIAAEEIIWNYAPSGIDIFTKENLTAPGSDSAVFFEQGTTRIGGSYKKLVYREYTDASFTNRKERGPEEEHLGILGPVIWAEVGDTIRVTFHNKGAYPLSIEPIGVRFNKNNEGTYYSPNYNPQSRSVPPSASHVAPTETFTYEWTVPKEVGPTNADPVCLAKMYYSAVEPTKDIFTGLIGPMKICKKGSLHANGRQKDVDKEFYLFPTVFDENESLLLEDNIRMFTTAPDQVDKEDEDFQESNKMHSMNGFMYGNQPGLTMCKGDSVVWYLFSAGNEADVHGIYFSGNTYLWRGERRDTANLFPQTSLTLHMWPDTEGTFNVECLTTDHYTGGMKQKYTVNQCRRQSEDSTFYLGERTYYIAAVEVEWDYSPQREWEKELHHLQEQNVSNAFLDKGEFYIGSKYKKVVYRQYTDSTFRVPVERKAEEEHLGILGPQLHADVGDKVKIIFKNMATRPYSIHAHGVQTESSTVTPTLPGETLTYVWKIPERSGAGTEDSACIPWAYYSTVDQVKDLYSGLIGPLIVCRRPYLKVFNPRRKLEFALLFLVFDENESWYLDDNIKTYSDHPEKVNKDDEEFIESNKMHAINGRMFGNLQGLTMHVGDEVNWYLMGMGNEIDLHTVHFHGHSFQYKHRGVYSSDVFDIFPGTYQTLEMFPRTPGIWLLHCHVTDHIHAGMETTYTVLQNEDTKSG。
在其他的实施例中，本领域技术人员可以采用与SEQ ID NO.1具有至少95％、96％、97％、98％或99％同源性的血浆铜蓝蛋白用于上述的(a)-(d)中任一项用途。
在可选的实施方式中，所述血浆铜蓝蛋白的种属来源为哺乳动物。
在可选的实施方式中，所述哺乳动物包括但不限于人、小鼠、大鼠、马、牛、猪、狗、猴、猿和羊。
在可选的实施方式中，所述炎症细胞包括CD4+T细胞；所述炎症因子为IL-17A+。
本发明的研究发现，给予血浆铜蓝蛋白后，EAE小鼠的CD4+T细胞和炎症因子IL-17A+浸润会减少，说明血浆铜蓝蛋白能够减少多发性硬化症的CD4+T细胞和IL-17A+浸润。
另一方面，本发明一种治疗多发性硬化症的药物的制备方法，其包括：以血浆铜蓝蛋白作为所述药物的主要活性成分。
基于本发明的研究结果，本领域技术人员在制备治疗多发性硬化症的药物时，可以想到使用血浆铜蓝蛋白为活性成分，并作为主要原料以制备治疗多发性硬化症的药物。因此，在药物的制备方法中，只要其目的是使添加的血浆铜蓝蛋白作为主要活性成分发挥治疗多发性硬化症的作用，即属于本发明的保护范围。
在可选的实施方式中，所述血浆铜蓝蛋白的氨基酸序列如SEQ ID NO.1所示或与其具有至少95％的同源性。
在可选的实施方式中，所述血浆铜蓝蛋白的种属来源为哺乳动物。
在可选的实施方式中，所述哺乳动物包括但不限于人、小鼠、大鼠、马、牛、猪、狗、猴、猿和羊。
在可选的实施方式中，所述药物还包括药学上可接受的辅料。本领域技术人员可以根据需要选用合适的辅料类型。
在可选的实施方式中，所述药物的剂型为注射剂。当然，在其他的一些实施方式中，本领域技术人员可以根据需要选用合适的剂型。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他相关的附图。
图1.血浆铜蓝蛋白能够减轻EAE模型小鼠临床评分。
图2.血浆铜蓝蛋白对EAE模型小鼠治疗具有剂量依赖性。
图3.血浆铜蓝蛋白能够减轻EAE小鼠的炎症浸润。
图4.血浆铜蓝蛋白能够减少EAE小鼠脱髓鞘。
图5.血浆铜蓝蛋白能够减轻EAE小鼠的神经元丢失。
图6.血浆铜蓝蛋白能够减少EAE小鼠脊髓内铁的积累。
图7.血浆铜蓝蛋白能够减少了EAE小鼠脊髓内脂质过氧化产物。
图8.血浆铜蓝蛋白可以部分逆转EAE小鼠T细胞稳态的异常。
图9.血浆铜蓝蛋白能够减少EAE小鼠T细胞效应细胞。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将对本发明实施例中的技术方案进行清楚、完整地描述。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产厂商者，均为可以通过市售购买获得的常规产品。实施例中涉及相关实验方法如HE染色、LFB染色、Nissl染色、铁离子水平、脂质氧化物、免疫细胞流式检测等均为本领域的常规检测方法。
以下结合实施例对本发明的特征和性能作进一步的详细描述。
实验动物：
小鼠：C57BL/6小鼠(6-8周龄，17-20g，雌性)，购于北京华阜康生物科技股份有限公司，所有小鼠均饲养于SPF(无特定病原体)级动物房。购买后，均适应性饲养一个星期后开始实验。饲养环境温度为22±2.0℃，相对湿度为55±15％，人工模拟昼夜节律(12小时光照/黑暗)，实验操作过程按《四川大学实验动物使用和管理条例》进行。
EAE模型小鼠构建的方法如下：
Day 0
1)用1×PBS稀释MOG储存液(MOG 35-55多肽，购自吉尔生化(上海)有限公司)至工作浓度为200μg/100μl，加入等体积CFA(含灭活结核杆菌10mg/ml)；
2)冰上来回推动注射器，充分乳化MOG/CFA混合物；
3)麻醉小鼠(8-9周，雌性C57)，肩部皮下注射MOG/CFA混合乳化物，左右各约100μl；
4)腹腔注射200ng pertussis toxin(百日咳毒素，购自Millipore)。
Day 2
5)48h后，二次注射pertussis toxin，200ng/只。
临床评分：模型建立12天，采用以下评分标准对实验小鼠进行临床评分：
| 0 | 无临床表型 |
| 0.5 | 尾巴部分无力下垂 |
| 1 | 尾巴完全无力下垂 |
| 2 | 运动能力失调，后肢轻度瘫痪 |
| 2.5 | 单个后肢瘫痪无力 |
| 3 | 双后肢瘫痪无力 |
| 3.5 | 后肢瘫痪，且前肢无力 |
| 4 | 前肢瘫痪 |
| 5 | 濒死或者死亡 |
实施例1
血浆铜蓝蛋白(Cp)改善EAE小鼠临床评分
血浆铜蓝蛋白(ceruloplasmin，Cp)是一种复杂的多组分氧化酶，在哺乳动物体内，ferroportin(Fpn)将Fe2+运输出细胞，由Cp氧化为Fe3+，结合transferrin(Tf)运输至血液中，对铁代谢过程有重要作用。
构建EAE模型13天后，不同临床评分EAE小鼠腹腔注射Cp(5mg/kg，SEQ ID NO.1)，隔天注射一次，每次注射Cp 5mg/kg，共注射7次，注射完成后，观察小鼠临床表型结果显示：临床评分1分、2分、2.5分、3分EAE小鼠，分别与EAE+saline小鼠相比得到显著改善(图1,P＝0.000399,P＜0.0001,P＜0.0001,P＝0.000154,Datameans±SEM,n＝7)；而临床评分4分以上小鼠无明显变化(图1，P＞0.05,Datameans±SEM,n＝7)。以上结果提示，Cp能够缓解不同病理进程EAE小鼠临床评分。构建EAE模型13天后，临床评分2-3分EAE小鼠给予不同剂量Cp注射，持续注射7天，观察临床表型结果显示：与EAE+saline小鼠相比，低剂量(1mg/kg，3mg/kg)注射EAE小鼠临床评分无明显改善(图2,P＝0.409701,P＝0.409701,Datameans±SEM,n＝7)；较高剂量(5mg/kg，7mg/kg)注射能减轻EAE小鼠临床症状(图2，P＜0.0001,P＜0.0001,Datameans±SEM,n＝7)；高剂量即10mg/kg以上注射，对小鼠产生致死毒性。以上结果提示，Cp能够缓解EAE小鼠病理进程，且具有剂量依赖性。
实施例2
血浆铜蓝蛋白改善EAE小鼠病理变化
临床评分3分左右的EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp5mg/kg，共注射7次，注射完成后，麻醉灌流4％多聚甲醛固定，完整取出全段脊髓，脊髓颈段制备石蜡切片，组化染色观察及分析。HE染色结果显示：注射Cp后小鼠与EAE小鼠相比得到显著改善，病灶明显减少(图3)。以上结果提示，Cp能够减少EAE小鼠脊髓炎症浸润。
临床评分3分左右的EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp5mg/kg，共注射7次，注射完成后，麻醉灌流4％多聚甲醛固定，完整取出全段脊髓，脊髓颈段制备石蜡切片，组化染色观察及分析。LFB染色结果显示：注射Cp后小鼠与EAE小鼠相比观察到脊髓脱髓鞘现象得以修复(图4)。以上结果提示，Cp能够改善EAE小鼠神经元脱髓鞘。
临床评分3分左右的EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp5mg/kg，共注射7次，注射完成后，麻醉灌流4％多聚甲醛固定，完整取出全段脊髓，脊髓颈段制备石蜡切片，组化染色观察及分析。Nissl染色结果显示：注射Cp后小鼠与EAE小鼠相比神经元数量明显增多(图5,P＝0.0124,Dataaremeans±SEM,n＝3)。以上结果提示Cp能够改善EAE小鼠神经元丢失。
取临床评分3分左右的EAE小鼠，腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp5mg/kg，共注射7次，注射完成后，立即处死，麻醉灌流固定后，完整取出小鼠脊髓，制备石蜡切片。通过对样品脊髓颈段切片染色，直观表现Cp注射后EAE小鼠的炎症浸润、脱髓鞘和神经元死亡情况。
结果显示，HE染色结果显示，Cp能降低EAE小鼠的炎症浸润；LFB染色结果显示，EAE小鼠的脱髓鞘现象得到改善；另外，尼氏染色(Nissl)的结果显示能Cp能减少EAE小鼠神经元死亡。
实施例3
血浆铜蓝蛋白能减低EAE小鼠体内脂质氧化物
临床评分3分左右EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp 5mg/kg，共注射7次，注射完成后，断颈处死立即取脊髓组织，ICP-MS金属离子分析结果显示：EAE小鼠铁离子水平显著高于对照组(图6,P＝0.0115,Data are means±SEM,n＝3)；Cp注射后，与EAE小鼠相比铁离子水平显著降低(图6,P＝0.0156,Data are means±SEM,n＝3)。以上结果提示，Cp能够改善EAE小鼠铁沉积。
临床评分3分左右EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp 5mg/kg，共注射7次。采用试剂盒检测脊髓和皮层组织匀浆液中MDA水平。脂质氧化物检测结果显示：与对照组相比，EAE小鼠脊髓存在显著脂质氧化物累积(Fig.32a,P＝0.0167,Datameans±SEM,n＝3)，Cp注射后，与EAE小鼠相比，脊髓脂质氧化物累积得到明显缓解(图7中a,P＝0.0603,Data means±SEM,n＝3)。同时，也检测了皮层中MDA水平，发现与对照组相比EAE小鼠无显著差异；Cp注射后，与EAE小鼠相比亦无明显差异(图7中b,P＞0.05,n＝3)。以上结果提示，Cp能够降低EAE小鼠脊髓脂质氧化物累积。
实施例4
血浆铜蓝蛋白减少EAE小鼠炎症浸润
构建EAE小鼠14天后，3分左右EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp 5mg/kg，共注射7次，注射完成后断颈处死，立即收集CNS区组织，梯度离心法取CNS区免疫细胞，检测T细胞增殖与分化。流式结果显示：Cp注射后与EAE小鼠相比，小鼠CD4+T细胞表达水平明显降低(图8中a,b,P＝0.0454,Data means±SEM,n＝3)，而CD8+T细胞无显著变化(图8中a,c,P＞0.05,Data means±SEM,n＝3)。以上结果提示，Cp能够减少CD4+T细胞增殖与分化。
构建EAE小鼠14天后，3分左右EAE小鼠腹腔注射Cp(5mg/kg)，隔天注射一次，每次注射Cp 5mg/kg，共注射7次，注射完成后，断颈处死立即收集CNS组织(包括大脑和脊髓)，梯度离心法取CNS免疫细胞，T细胞炎症因子增殖与分化。流式结果显示：Cp注射后与EAE小鼠相比，小鼠TH1(IFN-γ+)炎症因子无明显变化(图9中a,b,P＞0.05,Datameans±SEM,n＝3)；而TH17(IL-17A+)炎症因子表达水平显著降低(图9中a,c,P＝0.0338,Datameans±SEM,n＝3)。以上结果提示，Cp能够抑制T细胞炎症因子IL-17A+增殖。
综上实验结果，可以看出，血浆铜蓝蛋白对EAE模型小鼠具有明显的治疗改善效果，这些说明，血浆铜蓝蛋白可以用于治疗多发性硬化症的潜在新用途。本发明为多发性硬化症的治疗提供的新的药物选择和治疗策略。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
序列表
<110> 四川大学华西医院
<120> 血浆铜蓝蛋白在治疗多发性硬化症中的新用途
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<170> SIPOSequenceListing 1.0
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<211> 1065
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Ile Lys Ala Glu Thr Gly Asp Lys Val Tyr Val His Leu Lys Asn Leu
100 105 110
Ala Ser Arg Pro Tyr Thr Phe His Ser His Gly Ile Thr Tyr Tyr Lys
115 120 125
Glu His Glu Gly Ala Ile Tyr Pro Asp Asn Thr Thr Asp Phe Gln Arg
130 135 140
Ala Asp Asp Lys Val Tyr Pro Gly Glu Gln Tyr Thr Tyr Met Leu Leu
145 150 155 160
Ala Thr Glu Glu Gln Ser Pro Gly Glu Gly Asp Gly Asn Cys Val Thr
165 170 175
Arg Ile Tyr His Ser His Ile Asp Ala Pro Lys Asp Ile Ala Ser Gly
180 185 190
Leu Ile Gly Pro Leu Ile Ile Cys Lys Lys Asp Ser Leu Asp Lys Glu
195 200 205
Lys Glu Lys His Ile Asp Arg Glu Phe Val Val Met Phe Ser Val Val
210 215 220
Asp Glu Asn Phe Ser Trp Tyr Leu Glu Asp Asn Ile Lys Thr Tyr Cys
225 230 235 240
Ser Glu Pro Glu Lys Val Asp Lys Asp Asn Glu Asp Phe Gln Glu Ser
245 250 255
Asn Arg Met Tyr Ser Val Asn Gly Tyr Thr Phe Gly Ser Leu Pro Gly
260 265 270
Leu Ser Met Cys Ala Glu Asp Arg Val Lys Trp Tyr Leu Phe Gly Met
275 280 285
Gly Asn Glu Val Asp Val His Ala Ala Phe Phe His Gly Gln Ala Leu
290 295 300
Thr Asn Lys Asn Tyr Arg Ile Asp Thr Ile Asn Leu Phe Pro Ala Thr
305 310 315 320
Leu Phe Asp Ala Tyr Met Val Ala Gln Asn Pro Gly Glu Trp Met Leu
325 330 335
Ser Cys Gln Asn Leu Asn His Leu Lys Ala Gly Leu Gln Ala Phe Phe
340 345 350
Gln Val Gln Glu Cys Asn Lys Ser Ser Ser Lys Asp Asn Ile Arg Gly
355 360 365
Lys His Val Arg His Tyr Tyr Ile Ala Ala Glu Glu Ile Ile Trp Asn
370 375 380
Tyr Ala Pro Ser Gly Ile Asp Ile Phe Thr Lys Glu Asn Leu Thr Ala
385 390 395 400
Pro Gly Ser Asp Ser Ala Val Phe Phe Glu Gln Gly Thr Thr Arg Ile
405 410 415
Gly Gly Ser Tyr Lys Lys Leu Val Tyr Arg Glu Tyr Thr Asp Ala Ser
420 425 430
Phe Thr Asn Arg Lys Glu Arg Gly Pro Glu Glu Glu His Leu Gly Ile
435 440 445
Leu Gly Pro Val Ile Trp Ala Glu Val Gly Asp Thr Ile Arg Val Thr
450 455 460
Phe His Asn Lys Gly Ala Tyr Pro Leu Ser Ile Glu Pro Ile Gly Val
465 470 475 480
Arg Phe Asn Lys Asn Asn Glu Gly Thr Tyr Tyr Ser Pro Asn Tyr Asn
485 490 495
Pro Gln Ser Arg Ser Val Pro Pro Ser Ala Ser His Val Ala Pro Thr
500 505 510
Glu Thr Phe Thr Tyr Glu Trp Thr Val Pro Lys Glu Val Gly Pro Thr
515 520 525
Asn Ala Asp Pro Val Cys Leu Ala Lys Met Tyr Tyr Ser Ala Val Glu
530 535 540
Pro Thr Lys Asp Ile Phe Thr Gly Leu Ile Gly Pro Met Lys Ile Cys
545 550 555 560
Lys Lys Gly Ser Leu His Ala Asn Gly Arg Gln Lys Asp Val Asp Lys
565 570 575
Glu Phe Tyr Leu Phe Pro Thr Val Phe Asp Glu Asn Glu Ser Leu Leu
580 585 590
Leu Glu Asp Asn Ile Arg Met Phe Thr Thr Ala Pro Asp Gln Val Asp
595 600 605
Lys Glu Asp Glu Asp Phe Gln Glu Ser Asn Lys Met His Ser Met Asn
610 615 620
Gly Phe Met Tyr Gly Asn Gln Pro Gly Leu Thr Met Cys Lys Gly Asp
625 630 635 640
Ser Val Val Trp Tyr Leu Phe Ser Ala Gly Asn Glu Ala Asp Val His
645 650 655
Gly Ile Tyr Phe Ser Gly Asn Thr Tyr Leu Trp Arg Gly Glu Arg Arg
660 665 670
Asp Thr Ala Asn Leu Phe Pro Gln Thr Ser Leu Thr Leu His Met Trp
675 680 685
Pro Asp Thr Glu Gly Thr Phe Asn Val Glu Cys Leu Thr Thr Asp His
690 695 700
Tyr Thr Gly Gly Met Lys Gln Lys Tyr Thr Val Asn Gln Cys Arg Arg
705 710 715 720
Gln Ser Glu Asp Ser Thr Phe Tyr Leu Gly Glu Arg Thr Tyr Tyr Ile
725 730 735
Ala Ala Val Glu Val Glu Trp Asp Tyr Ser Pro Gln Arg Glu Trp Glu
740 745 750
Lys Glu Leu His His Leu Gln Glu Gln Asn Val Ser Asn Ala Phe Leu
755 760 765
Asp Lys Gly Glu Phe Tyr Ile Gly Ser Lys Tyr Lys Lys Val Val Tyr
770 775 780
Arg Gln Tyr Thr Asp Ser Thr Phe Arg Val Pro Val Glu Arg Lys Ala
785 790 795 800
Glu Glu Glu His Leu Gly Ile Leu Gly Pro Gln Leu His Ala Asp Val
805 810 815
Gly Asp Lys Val Lys Ile Ile Phe Lys Asn Met Ala Thr Arg Pro Tyr
820 825 830
Ser Ile His Ala His Gly Val Gln Thr Glu Ser Ser Thr Val Thr Pro
835 840 845
Thr Leu Pro Gly Glu Thr Leu Thr Tyr Val Trp Lys Ile Pro Glu Arg
850 855 860
Ser Gly Ala Gly Thr Glu Asp Ser Ala Cys Ile Pro Trp Ala Tyr Tyr
865 870 875 880
Ser Thr Val Asp Gln Val Lys Asp Leu Tyr Ser Gly Leu Ile Gly Pro
885 890 895
Leu Ile Val Cys Arg Arg Pro Tyr Leu Lys Val Phe Asn Pro Arg Arg
900 905 910
Lys Leu Glu Phe Ala Leu Leu Phe Leu Val Phe Asp Glu Asn Glu Ser
915 920 925
Trp Tyr Leu Asp Asp Asn Ile Lys Thr Tyr Ser Asp His Pro Glu Lys
930 935 940
Val Asn Lys Asp Asp Glu Glu Phe Ile Glu Ser Asn Lys Met His Ala
945 950 955 960
Ile Asn Gly Arg Met Phe Gly Asn Leu Gln Gly Leu Thr Met His Val
965 970 975
Gly Asp Glu Val Asn Trp Tyr Leu Met Gly Met Gly Asn Glu Ile Asp
980 985 990
Leu His Thr Val His Phe His Gly His Ser Phe Gln Tyr Lys His Arg
995 1000 1005
Gly Val Tyr Ser Ser Asp Val Phe Asp Ile Phe Pro Gly Thr Tyr Gln
1010 1015 1020
Thr Leu Glu Met Phe Pro Arg Thr Pro Gly Ile Trp Leu Leu His Cys
1025 1030 1035 1040
His Val Thr Asp His Ile His Ala Gly Met Glu Thr Thr Tyr Thr Val
1045 1050 1055
Leu Gln Asn Glu Asp Thr Lys Ser Gly
1060 1065
Claims (10)
1.血浆铜蓝蛋白在制备用于治疗多发性硬化症药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述血浆铜蓝蛋白的氨基酸序列如SEQ IDNO.1所示或与其具有至少95％的同源性。
3.根据权利要求1所述的应用，其特征在于，所述血浆铜蓝蛋白的种属来源为哺乳动物。
4.根据权利要求3所述的应用，其特征在于，所述哺乳动物选自人、小鼠、大鼠、马、牛、猪、狗、猴、猿和羊。
5.血浆铜蓝蛋白在制备具有如下(a)-(d)中任一项用途的药物中的应用：
(a)：用于改善多发性硬化症患者脱髓鞘现象；
(b)：用于减少发性硬化症患者神经元死亡；
(c)：用于降低多发性硬化症患者体内脂质氧化物含量；
(d)：用于减少多发性硬化症患者炎症细胞或炎症因子浸润。
6.根据权利要求5所述的应用，其特征在于，所述血浆铜蓝蛋白的氨基酸序列如SEQ IDNO.1所示或与其具有至少95％的同源性。
7.根据权利要求5所述的应用，其特征在于，所述血浆铜蓝蛋白的种属来源为哺乳动物。
8.根据权利要求7所述的应用，所述哺乳动物选自人、小鼠、大鼠、马、牛、猪、狗、猴、猿和羊。
9.根据权利要求5所述的应用，其特征在于，所述炎症细胞包括CD4+T细胞；所述炎症因子为IL-17A+。
10.一种治疗多发性硬化症的药物的制备方法，其特征在于，其包括：以血浆铜蓝蛋白作为所述药物的主要活性成分。
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| WO2022131791A1 (ko) * | 2020-12-17 | 2022-06-23 | 국립해양생물자원관 | 다중구리 산화효소 펩타이드를 포함하는 구리대사 관련 신경계 질환의 예방 또는 치료용 조성물 |
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