CN107812182A - 神经氨酸酶及抑制剂在制备抑制肝脏糖异生的药物中的应用 - Google Patents

神经氨酸酶及抑制剂在制备抑制肝脏糖异生的药物中的应用 Download PDF

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CN107812182A
CN107812182A CN201711201487.XA CN201711201487A CN107812182A CN 107812182 A CN107812182 A CN 107812182A CN 201711201487 A CN201711201487 A CN 201711201487A CN 107812182 A CN107812182 A CN 107812182A
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齐炼文
刘群
张蕾
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Abstract

本发明公开了神经氨酸酶及抑制剂在制备抑制肝脏糖异生的药物中的应用。已知扎那米韦、磷酸奥司他韦为神经氨酸酶的有效抑制剂，黄连碱对神经氨酸酶的抑制作用也已在申请人先前的专利申请中公开，申请人又发现丹酚酸B在体外可以抑制神经氨酸酶的活性，为神经氨酸酶的抑制剂；体内试验证明，这几种神经氨酸酶抑制剂可以有效抑制肝脏中神经氨酸酶活性，进而抑制肝脏糖异生。综上可见，神经氨酸酶及其抑制剂可用于制备抑制肝脏糖异生的药物，用于治疗糖尿病、肥胖和非酒精性脂肪肝。

Description

神经氨酸酶及抑制剂在制备抑制肝脏糖异生的药物中的应用
技术领域
本发明属于生物医药领域，涉及酶和酶抑制剂的应用，具体涉及神经氨酸酶及其抑制剂在制备抑制肝脏糖异生的药物中的应用。
背景技术
神经氨酸是广泛存在于生物体内的一类天然糖酸类化合物。现在确定神经氨酸有五十多种天然衍生物，N-乙酰神经氨酸、N-羟乙酰基神经氨酸是其中较为常见的衍生物。神经氨酸通常以短链残基的形式链接在糖蛋白、糖脂等糖缀合物的末端。神经氨酸是重要的生物信息传递分子，细胞表面糖蛋白和糖脂的神经氨酸化修饰在许多生物过程中发挥着至关重要的作用，包括细胞粘附、抗原识别和信号传导等。
在生物体内，神经氨酸酶是一种与神经氨酸相关的酶，在生物体内许多重要的生理过程中发挥着不可或缺的作用。神经氨酸酶可以断裂糖缀合物末端与神经氨酸残基相连接的糖苷键从而水解神经氨酸糖缀合物使得神经氨酸游离。
神经氨酸酶抑制剂是一类可以抑制神经氨酸酶活性的物质，如扎那米韦和磷酸奥司他韦。扎那米韦和磷酸奥司他韦是临床常用的治疗流感的药物。流感病毒通过其表面的红血球凝集素与宿主细胞表面的神经氨酸残基结合，继而侵入宿主细胞。随后，其基因在宿主细胞内复制和表达，形成新的流感病毒。在新病毒的释放阶段，神经氨酸酶催化水解成熟的流感病毒表面红血球凝集素与宿主细胞神经氨酸残基之间相连接的神经氨酸糖苷键，使得新病毒颗粒脱离被感染细胞，进一步在宿主体内扩散。扎那米韦和磷酸奥司他韦通过抑制神经氨酸酶的活性抑制新病毒颗粒脱离被感染细胞，抑制其在宿主体内扩散，达到治疗目的。
申请人于2016年3月22日提交了申请号为“201610166253.5”、发明名称为“神经氨酸酶及其抑制剂在心肌缺血及心肌梗死中的应用”的专利申请，该申请公开了神经氨酸酶及其抑制剂在心肌缺血及心肌梗死中的应用，提供了神经氨酸酶与心肌缺血损伤的关联性，证明通过抑制神经氨酸酶的活性可以缓解心肌缺血损伤，神经氨酸酶可以作为筛选预防、缓解和/或治疗心肌缺血损伤药物的靶标；该申请还证明了神经氨酸酶抑制剂对心肌缺血损伤的缓解作用，神经氨酸酶抑制剂通过降低神经氨酸酶的水平改善心肌缺血损伤。
申请人在随后的研究中还发现神经氨酸酶与多种疾病相关，经过检索，未发现现有技术公开过神经氨酸酶与这些疾病的相关性。
发明内容
本发明的目的在于提供神经氨酸酶及其抑制剂在制备抑制肝脏糖异生的药物中的应用。
本发明的上述目的是通过下面的技术方案得以实现的：
神经氨酸酶在制备抑制肝脏糖异生的药物中的应用。
神经氨酸酶在制备治疗糖尿病的药物中的应用。
神经氨酸酶在制备治疗肥胖的药物中的应用。
神经氨酸酶在制备治疗非酒精性脂肪肝的药物中的应用。
神经氨酸酶抑制剂在制备抑制肝脏糖异生的药物中的应用。
神经氨酸酶抑制剂在制备治疗肥胖的药物中的应用。
神经氨酸酶抑制剂在制备治疗肥胖的药物中的应用。
神经氨酸酶抑制剂在制备治疗非酒精性脂肪肝的药物中的应用。
黄连碱或丹酚酸B及其可药用盐用于制备神经氨酸酶抑制剂的用途。
扎那米韦、磷酸奥司他韦、黄连碱或丹酚酸B及其可药用盐用于制备抑制肝脏糖异生、治疗糖尿病、治疗肥胖或治疗非酒精性脂肪肝的药物中的用途。
已知扎那米韦、磷酸奥司他韦为神经氨酸酶的有效抑制剂，黄连碱对神经氨酸酶的抑制作用也已在申请人先前的专利申请中公开，申请人又发现丹酚酸B在体外可以抑制神经氨酸酶的活性，为神经氨酸酶的抑制剂；体内试验证明，这几种神经氨酸酶抑制剂可以有效抑制肝脏中神经氨酸酶活性，进而抑制肝脏糖异生。综上可见，神经氨酸酶及其抑制剂可用于制备抑制肝脏糖异生的药物，用于治疗糖尿病、肥胖和非酒精性脂肪肝。
附图说明
图1为各组小鼠肝脏糖异生率(％)；
图2为各组小鼠肝脏神经氨酸酶活性(U/μL)。
具体实施方式
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
实施例1：
将昆明种小鼠50只，按体重和性别随机均分为5组：对照组和扎那米韦、磷酸奥司他韦、黄连碱、丹酚酸B给药组。给药组小鼠分别给予0.2mg/kg/d的扎那米韦(i.v.)、5mg/kg/d磷酸奥司他韦(p.o.)、40mg/kg/d黄连碱(p.o.)、40mg/kg/d丹酚酸B(p.o.)，对照组灌胃给予等体积溶媒0.5％CMC-Na，连续给药4周。每组取7只用于测定糖异生率，具体方法为：末次灌胃后禁食12h后，尾静脉采血测空腹血糖，记作0min时血糖值；其后，按体重2g/kg剂量腹腔注射L-a-丙氨酸，1h后摘眼球取血，测60min时血糖值。根据0min和60min时血糖值计算糖异生率(％)。最后处死取肝，作肝糖元测定，用蒽酮硫酸法测肝糖原。
结果腹腔注射生糖氨基酸1h后，各组血糖都有升高，但对照组血糖升高幅度明显大于各给药组，依据各组0min和60min时血糖值计算糖异生率(％)，如下表和图1所示：
组别 肝脏糖异生率(％) 磷酸奥司他韦给药组 24.88±3.55
对照组 34.72±3.64 黄连碱给药组 27.96±3.82
扎那米韦给药组 26.55±3.73 丹酚酸B给药组 24.57±3.68
肝糖原测定结果显示，对照组肝糖原平均含量为0.55g/100g，扎那米韦、磷酸奥司他韦、黄连碱、丹酚酸B给药组肝糖原平均含量均在0.7g/100g以上，与对照组差异显著(P＜0.05)。
每组剩余3只用于测定肝脏神经氨酸酶活性，具体方法为：末次灌胃2h后，断头处死，迅速取出肝脏测定肝脏神经氨酸酶活性。具体方法为：小鼠断头处死，迅速取出肝脏，置于冰上，用冰冷的生理盐水冲洗干净，用滤纸吸干表面水分，称重，按500g/L的比例加入含0.25mmol/L蔗糖和1mmol/L EDTA的匀浆液匀浆，充分匀浆后将匀浆液离心，2000g×10min，将所得上清液进一步以78000g离心90min，取上清液，使用ELISA法检测大鼠肝脏神经氨酸酶水平，检测试剂盒为神经氨酸酶检测试剂盒(购自碧云天)，按照检测试剂盒的操作说明书进行测定。测定结果如下表和图2所示：
组别 神经氨酸酶活性(U/μL) 磷酸奥司他韦给药组 15.13±1.52
对照组 23.55±1.84 黄连碱给药组 17.32±1.63
扎那米韦给药组 16.21±1.46 丹酚酸B给药组 15.29±1.77
上述实施例证明，扎那米韦、磷酸奥司他韦、黄连碱、丹酚酸B在体内可以抑制神经氨酸酶的活性，通过抑制肝脏中神经氨酸酶的活性进而抑制肝脏糖异生。本领域技术人员知道，抑制肝脏糖异生可以治疗肥胖、非酒精性脂肪肝、糖尿病等疾病。
实施例2：
采用市售的神经氨酸酶抑制剂筛选试剂盒P0309(碧云天，Beyotime)对丹酚酸B进行体外抑制活性测试，阳性对照药为磷酸奥司他韦。在96孔板上每孔加入70μL缓冲液和10μL神经氨酸酶溶液，再加入10μL不同浓度的待测液，振动混匀，在37℃孵育5min，加入10μL含荧光底物的溶液，振动混匀，在37℃孵育30min，进行荧光测定，其中激发波长为322nm，发射波长为450nm。根据荧光读数计算出不同待测液的抑制率，并进一步获得阳性对照药磷酸奥司他韦和丹酚酸B的IC50值。结果如下表所示。
磷酸奥司他韦 丹酚酸B
IC50值(nmol/L) 13.5 195.5
上述实施例证明，丹酚酸B在体外可以抑制神经氨酸酶的活性，表现出中等强度的神经氨酸酶抑制活性，为神经氨酸酶的抑制剂。
已知扎那米韦、磷酸奥司他韦为神经氨酸酶的有效抑制剂，黄连碱对神经氨酸酶的抑制作用也已在申请人先前的专利申请中公开，申请人又发现丹酚酸B在体外可以抑制神经氨酸酶的活性，为神经氨酸酶的抑制剂；体内试验证明，这几种神经氨酸酶抑制剂可以有效抑制肝脏中神经氨酸酶活性，进而抑制肝脏糖异生。综上可见，神经氨酸酶及其抑制剂可用于制备抑制肝脏糖异生的药物，用于治疗糖尿病、肥胖和非酒精性脂肪肝。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。

Claims (10)

1.神经氨酸酶在制备抑制肝脏糖异生的药物中的应用。
2.神经氨酸酶在制备治疗糖尿病的药物中的应用。
3.神经氨酸酶在制备治疗肥胖的药物中的应用。
4.神经氨酸酶在制备治疗非酒精性脂肪肝的药物中的应用。
5.神经氨酸酶抑制剂在制备抑制肝脏糖异生的药物中的应用。
6.神经氨酸酶抑制剂在制备治疗肥胖的药物中的应用。
7.神经氨酸酶抑制剂在制备治疗肥胖的药物中的应用。
8.神经氨酸酶抑制剂在制备治疗非酒精性脂肪肝的药物中的应用。
9.黄连碱或丹酚酸B及其可药用盐用于制备神经氨酸酶抑制剂的用途。
10.扎那米韦、磷酸奥司他韦、黄连碱或丹酚酸B及其可药用盐用于制备抑制肝脏糖异生、治疗糖尿病、治疗肥胖或治疗非酒精性脂肪肝的药物的用途。
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CN115040502B (zh) * 2022-06-09 2023-07-04 海南大学 一种海洋曲霉菌来源化合物的应用

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