CN107737133B - 非达霉素在制备治疗寨卡病毒感染引起的相关疾病和/或症状的药物中的应用 - Google Patents
非达霉素在制备治疗寨卡病毒感染引起的相关疾病和/或症状的药物中的应用 Download PDFInfo
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Abstract
本发明公开了非达霉素在制备治疗寨卡病毒感染引起的相关疾病和/或症状的药物中的应用,非达霉素作为已经被临床批准使用的抗艰难梭菌感染药物,安全性高,且非达霉素抑制寨卡病毒活性高,与寨卡病毒非结构蛋白NS5有较强的结合能力,有望成为新的有效的抗寨卡病毒感染药物。
Description
技术领域
本发明属于医药领域,更具体地,涉及非达霉素在制备治疗寨卡病毒感染引起的相关疾病和/或症状的药物中的应用。
背景技术
非达霉素(Fidaxomicin)(商品名为Dificid,亦称difimicin,lipiarmycin,tiacumicin B,曾用名:PAR-101,OPT-80)是一种细菌的DNA依赖性的RNA酶抑制剂。由Optimer公司研制用于初始治疗艰难梭菌感染(Clostridium difficile infection,CDI)及预防CDI复发,2011年1月,美国食品和药物管理局(FDA)通过了非达霉素用于治疗小儿CDI的资格申请,2011年5月,FDA批准了非达霉素用于成人CDI治疗。
寨卡病毒属于黄病毒科黄病毒属,是RNA正链病毒,通过蚊虫传播,可通过性传播。感染者可出现全身性发热、出疹、关节炎和脑炎等症状。令人关注的,寨卡病毒会引起格林-巴利综合征、新生儿小头症。
ZIKV-NS5是一种RNA依赖性的RNA聚合酶,行使病毒基因组复制功能,对病毒复制起到至关重要作用,抑制该种酶活性可以达到杀灭寨卡病毒的效果。
目前针对寨卡病毒,缺少临床批准的有效药物。
发明内容
本发明的目的在于根据现有技术中的不足,提供了非达霉素在制备抑制寨卡病毒药物中的应用。
本发明通过以下技术方案实现上述技术目的:
本发明提供了非达霉素在制备抑制寨卡病毒药物中的应用。
进一步地,非达霉素是在制备治疗寨卡病毒感染引起的相关疾病和/或症状的药物中的应用。
进一步地,非达霉素是作为寨卡病毒非结构蛋白NS5(DENV-NS5)抑制剂,发挥抑制寨卡病毒的作用。
更进一步地,非达霉素作为RNA依赖性的RNA酶(DENV-NS5 RdRp)抑制剂。
所述药物还包括药学上可接受的盐或载体。
本发明在体内外验证了非达霉素对于寨卡病毒的抑制活性,结果显示,非达霉素在体内外均具备显著的抑制寨卡病毒活性效果,且高浓度的剂量没有明显毒副作用。
与现有技术相比,本发明具有如下优点和有益效果:
本发明提供了非达霉素作为抑制寨卡病毒上的新应用,非达霉素作为已经被临床批准使用的抗艰难梭菌感染药物,安全性高,且非达霉素在细胞水平上抑制寨卡病毒活性高,与DENV2-NS5蛋白有较强的结合能力,有望成为新的有效的抗寨卡病毒感染药物。
附图说明
图1为非达霉素在A549细胞中抑制ZIKV NS3蛋白。
图2为非达霉素抑制小鼠脾脏ZIKV的复制。
图3为非达霉素50μM浓度下对ZIKV RdRp酶活性的抑制。
具体实施方式
以下结合具体实施例和附图来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,本发明所用试剂和材料均为市购。
实施例1:非达霉素在细胞水平上的抑制ZIKV活性
病毒株:寨卡病毒ZIKV(Z16019)
细胞系:A549
检测方法:
非达霉素抗病毒半数有效剂量(50% Effective Concentration,EC50):DMSO,6、9、12、18、24μM非达霉素提前1h饱和细胞,病毒感染2h后,换含对应浓度药物的无病毒培养基维持48h;收集细胞上清,用空斑实验检测病毒感染后非达霉素不同剂量组相对溶剂组(DMSO)的空斑形成抑制率。
抑制率(%) = (1-给药组病毒空斑形成数/溶剂对照组空斑形成数)100%,用EXCEL2013的Forcast公式计算,当抑制率等于50%时,对应非达霉素的浓度,作为EC50。三次重复实验取平均值。
非达霉素细胞毒半数细胞活性抑制剂量(50% Cytotoxcitive Concentration,CC50):MTT法,非达霉素梯度剂量加入到A549细胞上清中,维持48h后加入MTT孵育4h,吸出培养基,加入DMSO检测490nm出吸光度值与DMSO溶剂对照组进行比较,计算抑制剂率(%)=(1-给药组490nm吸光度值/溶剂对照组490nm吸光度值)100%,用EXCEL 2013的Forcast公式计算,当抑制率等于50%时,对应非达霉素的浓度,作为CC50。三次重复实验取平均值。得出结果表1:
表1:非达霉素在A549细胞中抑制ZIKV EC50及CC50
antiviral EC50(μM) | CC50(μM) | |
ZIKV(Z16019) | A549 | |
Fidaxomicin | 18.91±1.62 | 70.84±4.72 |
实施例2非达霉素在A549细胞系中对ZIKV-NS3蛋白的抑制活性
病毒株:寨卡病毒ZIKV(Z16019)
细胞系:A549
检测方法:
DMSO,10、50、100μM非达霉素提前1h饱和细胞,病毒感染2h后,换含对应浓度药物的无病毒培养基维持48h;收集细胞沉淀,用蛋白质免疫印迹电泳检测不同处理下细胞内ZIKV-NS3蛋白的相对表达量,以GAPDH作为内参蛋白。如图1所示,非达霉素在10~50μM即可有效抑制ZIKV NS3蛋白表达,进而阻止ZIKV的繁殖。
实施例3非达霉素在小鼠体内的抗ZIKV活性
小鼠品系:C57BL/6J WT
模型:anti-IFNAR1抗体封闭法
实验方法:5~6W小鼠提前一天腹腔注射抗体,当天腹腔感染ZIKV 1×105PFU病毒4h后腹腔给药,设置Mock组、溶剂对照组、非达霉素剂量30、75、150mg/kg剂量组,连续给药7天,第8天处死小鼠解剖取脾脏,qRT-PCR方法检测脾脏中ZIKV病毒RNA拷贝数。结果如图2,在小鼠体内,75mg/kg、150mg/kg剂量下具有明显抗ZIKV效果(p<0.01)。对应在150mg/kg剂量连续7天给药没有死亡,75mg/kg剂量没有明显毒副作用。
实施例4非达霉素在50μM浓度下对ZIKV-NS5酶的抑制活性
体外合成带有Cy5标记的20nt的RNA primer和无标记的28nt的RNA Template,在纯化出ZIKV-NS5蛋白作用下,可以进行RNA聚合反应,产生28nt带Cy5标记的RNA产物,用尿素胶进行电泳分离,化学发光并记录Cy5标记条带的位置。结果显示非达霉素在50μM浓度完全抑制不同浓度的ZIKV-NS5的RNA复制活性,也即抑制了寨卡病毒RNA依赖性RNA聚合酶活性。结果如图3。
Claims (3)
1.非达霉素在制备抑制寨卡病毒药物中的应用。
2.根据权利要求1所述的应用,其特征在于,非达霉素作为寨卡病毒非结构蛋白NS5抑制剂。
3.根据权利要求1所述的应用,其特征在于,所述药物包括药学上可接受的盐或载体。
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Anilrudh A. Venugopal等.Fidaxomicin: A Novel Macrocyclic Antibiotic Approved for Treatment of Clostridium difficile Infection.《Clinical Infectious Diseases》.2012,第54卷(第4期),第568-574页. * |
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