CN114767707B - 包含低分子壳聚糖的用于预防或治疗冠状病毒感染疾病的组合物 - Google Patents
包含低分子壳聚糖的用于预防或治疗冠状病毒感染疾病的组合物 Download PDFInfo
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Abstract
本发明涉及包含低分子壳聚糖或壳寡糖的用于预防或治疗冠状病毒感染疾病的组合物,更详细地,涉及包含针对严重急性呼吸综合征冠状病毒2(SARS‑CoV‑2,Severe acute respiratory syndrome coronavirus2)表现出抗病毒功效的特定分子量范围的低分子壳聚糖或壳寡糖的用于预防或治疗冠状病毒感染疾病的组合物。包含特定分子量范围的低分子壳聚糖或壳寡糖的本发明的组合物可抑制严重急性呼吸综合征冠状病毒2的翻译、复制、增殖,并可有效预防或治疗因感染严重急性呼吸综合征冠状病毒2引起的新型冠状病毒肺炎(COVID‑19)。
Description
技术领域
本发明涉及包含低分子壳聚糖或壳寡糖的用于预防或治疗冠状病毒感染疾病的组合物,更详细地,涉及包含针对严重急性呼吸综合征冠状病毒2(SARS-CoV-2,Severeacute respiratory syndrome coronavirus 2)表现出抗病毒功效的特定分子量范围的低分子壳聚糖或壳寡糖的用于预防或治疗冠状病毒感染疾病的组合物。
背景技术
传染性疾病为因菌、细菌、病毒等异物开始出现并栖息在血液、体液及组织中而发生的疾病,若无法精确鉴别其并进行适当治疗,则有可能失去生命。虽然,传染疾病的流行率随着卫生水平的提高而处于下降的趋势,但是,随着抗生素的滥用、因移植导致的免疫抑制剂使用增加、因抗癌治疗导致的免疫力下降、患有糖尿病、高血压等基础疾病的人数增加等,导致致命结果的感染疾病的威胁呈增加的趋势。
尤其,大部分感染疾病伴随着感染部位的炎症反应,其中一部分因引起全身炎症反应而导致致命后果。并且,由于感染引起的感染患者可能会死亡,因此,尽快开始进行适当的抗生素治疗尤为重要,为此,需通过精确的诊断和预测严重程度来保障感染患者的生存。
能够感染人的人冠状病毒有在1960年代发现的人冠状病毒229E(HCoV-229E)和HCoV-OC43及非典流行后发现的HCoV-NL63(2004年)和HCoV-HKUl(2005年),众所周知,上述病毒均与上呼吸道感染疾病有关,但对于免疫缺陷患者而言,可导致严重的肺部疾病。据报告,冠状病毒的感染率主要在冬季或早春增加,而在成人感冒患者中以冠状病毒作为病原体发病的比例相当高。随着在2003年首次发现诱发严重急性呼吸综合征(SARS,SevereAcute Respiratory Syndrome)的严重急性呼吸综合征冠状病毒(SARS-CoV),根据世界卫生组织(WHO)的报告,在2002年至2003年之间,全世界发生8273名患者和775名死亡人员(死亡率约为10%),直至2004年还发生额外的患者和死亡人员。
在2012年9月发现与严重急性呼吸综合征冠状病毒感染疾病相似的发生高热、咳嗽、呼吸困难等呼吸道症状的重症呼吸道疾病患者,结果发现其原因病原体为不同于现已知病毒的新型冠状病毒(HCoV-EMC)。
在2013年5月,国际病毒分类委员会(International Committee on TaxonomyofViruses)的冠状病毒研究小组将新型冠状病毒冠以“中东呼吸综合征冠状病毒(MERS-CoV)”的名称进行了分类。
在2012年9月,在沙特阿拉伯首次确认中东呼吸综合征冠状病毒(MERS-CoV)感染病例后,据世界卫生组织(WHO)公开报告显示,截止2014年6月,全世界共发生808名患者和313名死亡人员(34.5%)。
另一方面,随着最近2019年新型人冠状病毒在全世界迅速扩散,已对世界健康构成威胁。SARS-CoV-2(Severe acute respiratory syndrome coronavirus 2)为在2019年首次出现的严重急性呼吸综合征冠状病毒2,被分类为阳性单链RNA病毒(positive-sensesingle-stranded RNA virus)。将被这种病毒感染的疾病称为“新型冠状病毒肺炎(Coronavirus disease 2019)”,简称为COVID-19。随着世界卫生组织(WHO,World HealthOrganization)公开发布冠状病毒大流行(Coronavirus pandemic),据调查,截止2020年12月,当前韩国的感染人数已接近6万5千名,全世界感染人数约有8千5百万名,并且,呈持续扩散的趋势。
虽然,当前还没有韩国食品药物管理局(KFDA)所批准的治疗剂,但存在以治疗为目的承认使用的产品和正进行临床试验的产品。美国食品药品监督管理局(FDA)已正式将埃博拉病毒治疗剂的瑞德西韦(Remdesivir)批准为新型冠状病毒肺炎的治疗剂。但是,以往周知的瑞德西韦、作为人类免疫缺陷病毒(HIV)治疗剂的克力芝(Kaletra)、作为疟疾治疗剂的氯喹(Chloroquine)等高分子或化学物质治疗剂具备治疗效果的同时伴随着严重的副作用,然而,在本发明中使用的作为安全的天然材料并能够食用的低分子壳聚糖或壳寡糖不仅对严重急性呼吸综合征冠状病毒2有效,而且,具有无副作用或副作用较少的优点。
因此,当前急需开发能够有效预防或治疗冠状病毒感染疾病的治疗剂。
发明内容
对此,本发明人为了寻找能够治疗冠状病毒感染疾病的天然源物质而进行研究,结果发现在规定的分子量范围的低分子壳聚糖或壳寡糖能够对冠状病毒表现出强力的抗病毒作用并能够将其用于预防冠状病毒的感染或治疗剂,从而完成了本发明。
因此,本发明的目的在于,提供包含低分子壳聚糖或壳寡糖作为有效成分的用于预防或治疗冠状病毒感染疾病的药物组合物。
本发明的再一目的在于,提供包含低分子壳聚糖或壳寡糖作为有效成分的用于预防或改善冠状病毒感染疾病的食品组合物。
本发明的另一目的在于,提供包含低分子壳聚糖或壳寡糖作为有效成分的针对冠状病毒的抗病毒组合物。
为了实现本发明的上述目的,本发明提供用于预防或治疗冠状病毒感染疾病的药物组合物,其包含低分子壳聚糖或壳寡糖作为有效成分。
为了实现本发明的再一目的,本发明提供用于预防或改善冠状病毒感染疾病的食品组合物,其包含低分子壳聚糖或壳寡糖作为有效成分。
为了实现本发明的另一目的,本发明提供针对冠状病毒的抗病毒组合物,其包含低分子壳聚糖或壳寡糖作为有效成分。
以下,详细说明本发明。
本发明提供用于预防或治疗冠状病毒感染疾病的药物组合物,其包含低分子壳聚糖或壳寡糖作为有效成分。
在本发明中,上述壳聚糖为截掉甲壳素的乙酰基(CH3CO-)的形态,是指5000个以上的D-氨基葡萄糖反复结合的高分子天然多糖体,低分子壳聚糖为由2个~500个D-氨基葡萄糖连接而成的低聚糖,是指具有加强生理活性和体内吸收率的高功能天然多糖类,具备壳聚糖和低聚糖的所有特性。通常称为低分子壳聚糖的特征在于,通过酶或盐酸处理高分子壳聚糖来缩短D-氨基葡萄糖的结合并实现分子量的低分子化。壳聚糖属于分子量为几十万道尔顿到几百万道尔顿的高分子量多糖类。由于分子量非常大且结构难以破坏,在肠胃不易被分解,体内吸收的仅为3%左右。如上所述,即使体内吸收率低且溶解度低而具有优秀的生理活性,其应用范围也受限。相反,由于低分子壳聚糖相比于高分子量壳聚糖具有更高的抗菌、抗氧化、溶解性及渗透性等特性,可更快、更轻易渗透到细菌膜并表现出较高的抗菌活性和抗氧化活性。利用这种特性,进行了将低分子壳聚糖用作生物刺激剂、抗菌物质、抗菌剂及抗氧化剂的诸多研究,可广泛用于食品、健康及农业领域等。
在本发明中,上述低分子壳聚糖是指平均分子量为80000Da以下的壳聚糖,上述低分子壳聚糖包括壳寡糖。优选地,上述低分子壳聚糖的平均分子量为400Da至80000Da,更优选地,平均分子量为10000Da至50000Da,更加优选地,平均分子量为15000Da至45000Da,最优选地,壳聚糖的平均分子量可以为25000Da至35000Da。
在本发明中,上述壳寡糖为使得人体更加轻易吸收高分子量的壳聚糖而制备的低分子水溶性壳聚糖,可将蟹、虾壳等通过脱蛋白(去除蛋白质)、脱钙(去除钙)、洗涤、干燥等工序来提纯为甲壳素后经过脱乙酰化制备壳聚糖,随后,可通过对上述壳聚糖进行利用盐酸等无机酸的化学分解方法或利用酶的分解方法来获得。例如,在利用酶的分解方法中,向壳聚糖添加蒸馏水后,通过添加2%~3%的盐酸(以壳聚糖底物浓度5%为基准,相对于水量的盐酸原液为2%,相对于壳聚糖量的盐酸原液量约为40%)并在40℃~60℃的温度条件下进行搅拌来制备包含5%~10%盐酸的壳聚糖水溶液。完全溶解后,将pH值调节为4~6,并将作为壳聚糖分解酶的壳聚糖水解酶加入并溶解在蒸馏水中。接着,在40℃~60℃的温度条件下,水解14小时~20小时后,在80℃的温度条件下,通过热处理30分钟来使酶失活,随后,可通过过滤干燥工序来获得壳寡糖。在如上所述的制备工序中,上述壳寡糖的分子量基于壳聚糖水解酶的添加量和水解时间产生变化。
在本发明中,上述壳寡糖的平均分子量为400Da至80000Da,更优选地,平均分子量为10000Da至50000Da,更加优选地,平均分子量为15000Da至45000Da,最优选地,壳寡糖的平均分子量可以为25000Da至35000Da。
根据本发明的一实施例,已确认低分子壳聚糖或壳寡糖可抑制对于冠状病毒的病源性必不可少的RNA依赖性RNA聚合酶(RdRp,RNA-dependent RNA polymeras)、包膜(envelope,E)及核衣壳(nucleocapsid,N)的基因表达,其中,示出表达30000Da分子量的低分子壳聚糖或壳寡糖显著提高的效果。
在本发明中,上述冠状病毒感染疾病可以选自由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染疾病、严重急性呼吸综合征冠状病毒(SARS-CoV)感染疾病及中东呼吸综合征冠状病毒(MERS-CoV)感染疾病组成的组中,最优选为严重急性呼吸综合征冠状病毒2感染疾病(COVID-19)。
上述严重急性呼吸综合征冠状病毒2为可感染人类和各种动物的病毒,属于基因大小为27kb~32kb的RNA病毒。冠状病毒感染疾病的潜伏期约为2周,以伴随发热的咳嗽、呼吸困难、气短、痰多等呼吸道症状为主,除此之外,还可表现出头痛、发冷、流鼻涕、肌肉痛以及食欲不振、恶心、呕吐、腹痛、腹泻等消化系统症状。本发明的上述药物组合物可有效预防或治疗在冠状病毒感染疾病中显示出的上述各种症状。
并且,本发明提供的上述分子量的低分子壳聚糖或壳寡糖抑制冠状病毒的翻译、复制、增殖,因此,可用作针对冠状病毒的抗病毒剂,对此,在本发明的另一观点中,涉及包含低分子壳聚糖或壳寡糖的药学上可接受的盐作为有效成分的针对冠状病毒的抗病毒组合物。
在本发明的组合物中,低分子壳聚糖或壳寡糖可使用其本身或以盐的形态使用,优选地,能够以药学上可接受的盐的形态使用。本发明中的“药学上可接受”是指在生理学上接受,且当向人体给药时,通常不会引起过敏反应或与其相似的反应,优选地,上述盐为通过药学上可接受的游离酸(free acid)形成的酸加成盐。可使用有机酸或无机酸作为上述游离酸。上述有机酸可包括柠檬酸、醋酸、乳酸、酒石酸、马来酸、富马酸、甲酸、丙酸、草酸、三氟乙酸、苯甲酸、葡萄糖酸、甲磺酸、乙醇酸、琥珀酸、4-甲苯磺酸、谷氨酸和天门冬氨酸,但并不限定于此。并且,上述无机酸包括盐酸、溴酸、硫酸及磷酸,但并不限定于此。
为了治疗病毒感染疾病,本发明的药物组合物可通过所属领域的公知方法并根据给药途径与药学上可接受的载体一同剂型化为各种剂型。作为上述载体可包括所有种类的溶剂、分散介质、水包油或油包水型乳剂、水性组合物、脂质体、微珠及微粒体。
本发明的上述药物组合物可向患者给药足以预防或缓解症状并治疗病毒感染疾病的量,即,药学有效量。例如,通常一日剂量可在约0.01mg/kg至1000mg/kg的范围内给药,优选地,可以在约1mg/kg至100mg/kg的范围内给药。本发明的药物组合物可在优选剂量范围内给药一次或分多次给药。并且,普通技术人员可根据给药途径、给药对象、年龄、性别体重、个体差异及疾病状态适当选择本发明药物组合物的剂量。
作为给药途径,可口服给药或肠胃外给药。作为肠胃外给药方法有静脉内、肌肉内、动脉内、骨髓内、硬膜内、心脏内、透皮、皮下、腹腔内、鼻腔内、肠道、关节、舌下、直肠或胰腺内给药,但并不限定于此,最优选地,可口服给药。
当口服给药本发明的药物组合物时,可通过所属领域的公知方法与适合口服给药的载体一同配制为粉末、颗粒、片剂、丸剂、糖衣片剂、胶囊剂、液剂、胶剂、糖浆剂、悬浮剂、晶片等的形态。作为适合的载体包括:糖类,如乳糖、右旋糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇及麦芽糖醇等;淀粉类,如玉米淀粉、小麦淀粉、大米淀粉及马铃薯淀粉等;以及纤维素类,如纤维素、甲基纤维素、羧甲基纤维素钠及羟丙基甲基纤维素等;以及填充剂,如明胶、聚乙烯吡咯烷酮等。并且,可根据情况添加交联聚乙烯吡咯烷酮、琼脂、海藻酸或海藻酸钠等作为崩解剂。而且,本发明的药物组合物还可包含抗凝剂、润滑剂、润湿剂、香料、乳化剂及防腐剂等。
并且,当非口服给药时,本发明的药物组合物可通过所属领域的公知方法与适合非口服的载体一同配制为注射剂、透皮给药剂及鼻腔吸入剂等的形态。
并且,药物组合物可通过使活性物质能够向靶细胞移动的任意装置给药。优选的给药方式及制剂为静脉注射剂、皮下注射剂、皮内注射剂、肌肉注射剂或滴点注射剂等。注射剂可利用如生理盐水或林格氏液等水性溶剂、如植物油、高级脂肪酸酯(例如,油酸乙酯等)、醇类(例如,乙醇、苯甲醇、丙二醇或甘油等)等非水性溶剂等制备,可包含用于防止变质的稳定剂(例如,抗坏血酸、亚硫酸氢钠、焦亚硫酸钠、丁基羟基茴香醚(BHA)、生育酚、乙二胺四乙酸(EDTA)等)、乳化剂、用于调节pH值的缓冲剂、用于抑制微生物生长的保鲜剂(例如,硝酸苯汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苯甲醇等)等药物载体。
上述注射剂必须经过灭菌处理,防止被如细菌、真菌等微生物污染。在注射剂的情况下,适合的载体可例举水、乙醇、多元醇(例如,甘油、丙二醇及液体聚乙二醇等)、它们的混合物和/或包含植物油的溶剂或分散介质,但并不限定于此。更优选地,适合的载体可使用Hanks溶液、林格溶液、包含三乙醇胺的磷酸盐缓冲液(PBS,Phosphate bufferedsaline)或注射用无菌水、10%乙醇、40%丙二醇及5%葡萄糖等等渗溶液。为了保护上述注射剂免受于微生物污染,还可额外包含多种抗菌剂和抗真菌剂,例如,对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。并且,在大多数情况下,上述注射剂还可包含等渗化剂,例如,糖或氯化钠。
除此之外的药学上可接受的载体可参照以下文献中记载的内容(Remington’sPharmaceutical Sciences,19th ed.,Mack Publishing Company,Easton,PA,1995)。
本发明的药物组合物还可包含一种以上的缓冲剂(例如,盐水或磷酸盐缓液)、碳水化合物(例如,葡萄糖、甘露糖、蔗糖或葡聚糖)、抗氧化剂、抑菌剂、螯合剂(例如,乙二胺四乙酸或谷胱甘肽)、佐剂(例如,氢氧化铝)、悬浮剂、增稠剂和/或保鲜剂。
并且,本发明的药物组合物可通过使用所属领域的公知方法配制,以向哺乳动物给药后能够迅速、持续或延迟提供活性成分的释放。
并且,本发明的药物组合物可单独给药,或者,可以与具有治疗病毒感染疾病效果的公知化合物结合给药。
本发明还提供包含低分子壳聚糖或壳寡糖作为有效成分的用于预防或改善冠状病毒感染疾病的食品组合物。
本发明的食品组合物包括功能食品(functional food)、营养补充剂(nutritional supplement)、保健食品(health food)及食品添加剂(foodadditives)等所有形态。
以上类型的食品组合物可通过所属领域中通常使用的公知方法制备成多种形态。例如,保健食品可通过对低分子壳聚糖或壳寡糖进行液体化、颗粒化、胶囊化及粉末化来摄取,以制成茶、果汁及饮料等形态来饮用,但并不限定于此。并且,可通过一同混合低分子壳聚糖或壳寡糖与具有抗病毒效果的已公知的活性成分来制备成组合物形态。并且,功能食品可通过向饮料(包括酒精饮料)、水果及其加工食品(例如,水果罐头、瓶装罐头、果酱、橘子酱等)、鱼类、肉类及其加工食品(例如,火腿、玉米牛肉香肠等)、面包类及面类(例如,乌冬面、荞麦面、拉面、意大利面、通心粉等)、果汁、各种饮料、饼干、饴糖、乳制品(例如,黄油、奶酪等)、食用植物油、人造黄油、植物蛋白、软罐头、冷冻食品、各种调味料(例如,大酱、酱油、酱汁等)等添加低分子壳聚糖或壳寡糖来制备,但并不限定于此。并且,低分子壳聚糖或壳寡糖可被制备成粉末或浓缩液形态,以便用作添加剂。
优选地,在本发明的食品组合物中,在最终制备的食品所包含的低分子壳聚糖或壳寡糖为0.1重量百分比至100重量百分比,但并不限定于此。更优选地,本发明包含低分子壳聚糖或壳寡糖作为有效成分的食品组合物可通过与具有抗病毒效果的已知活性成分一同混合来制备保健功能食品或膳食补充剂。
本发明还提供包含低分子壳聚糖或壳寡糖作为有效成分的针对冠状病毒的抗病毒组合物。
在本发明中,上述抗病毒组合物包括除上述药物组合物及食品组合物外的所有组合物,作为其的非限制性示例,可包括抗病毒用化妆品组合物、抗病毒用皮肤外用剂组合物、抗病毒用准药品组合物等。
在上述组合物为化妆品组合物或皮肤外用剂组合物的情况下,适合的剂型可例举溶液、凝胶、固体或搅拌无水生成物、通过向水相分散油相获得的乳液、悬浮液、微乳液、微胶囊、微颗粒或离子型(脂质体)、非离子型囊泡分散剂形态、面霜、化妆水、粉末、软膏或喷雾剂形态。并且,也可制备成泡沫(Foam)形态或还包含压缩的推进剂的气溶胶组合物形态。
在上述化妆品组合物或皮肤外用剂组合物中,化合物还可包含脂肪物质、有机溶剂、溶解剂、浓缩剂及凝胶剂、软化剂、抗氧化剂、悬浮剂、稳定剂、发泡剂(Foaming agent)、芳香剂、表面活性剂、水、离子乳化剂或非离子乳化剂、填充剂、金属离子螯合剂及螯合剂、保鲜剂、维生素、阻断剂、润湿剂、精油、染料、颜料、亲水性或亲油性活性剂、脂质囊泡或如通常用于皮肤外用剂的任意其他成分的在皮肤科学领域中通常使用的助剂。并且,可根据在皮肤科学领域中通常使用的量采用上述成分。
另一方面,在上述组合物为准药品组合物的情况下,可直接添加低分子壳聚糖或壳寡糖,或者,也可以与其他准药品或准药品成分一同使用,可按照通常方法适当混合使用。有效成分的混合量可根据使用目的作出适当决定。
作为一例,上述准药品可以为消毒清洁剂、沐浴露、漱口水、湿巾、肥皂、洗手液、加湿器填充剂、面膜、软膏剂、贴片或过滤器填充剂,但并不限定于此。
在日常生活中,本发明提供的上述抗病毒组合物可用于预防冠状病毒感染。
将本发明的包含特定分子量范围的低分子壳聚糖或壳寡糖的组合物用作食用,由此可安全地抑制严重急性呼吸综合征冠状病毒2的翻译、复制、增殖,并可在没有副作用的情况下有效预防或治疗因严重急性呼吸综合征冠状病毒2感染引起的冠状病毒感染疾病。
附图说明
图1为示出使用溶剂对照组和壳寡糖处理猴源Vero E6细胞并观察细胞毒性的结果图。
图2为示出为了筛选用于实验的严重急性呼吸综合征冠状病毒2而使得Vero E6细胞感染6种严重急性呼吸综合征冠状病毒2并观察细胞是否变性的结果图。
图3为示出确认多种分子量的壳寡糖对于严重急性呼吸综合征冠状病毒2的抗病毒作用的结果图。
图4为示出确认壳寡糖对除严重急性呼吸综合征冠状病毒2以外的其他冠状病毒(人冠状病毒229E)是否具有相同抗病毒作用的结果图。
图5为示出为了确认壳寡糖对于严重急性呼吸综合征冠状病毒2增殖的抑制效果而进行菌斑分析(plaque assay)的结果图。
图6为示出作为比较例将壳聚糖与严重急性呼吸综合征冠状病毒2反应1小时,并使Vero细胞感染病毒2天后观察干涉病毒合成的基因的表达的结果图。
具体实施方式
以下,通过以下实施例详细说明本发明。但是,以下实施例仅用于例示本发明,本发明并不限定于此。
1.壳寡糖(15kDa)的宿主细胞内毒性观察
为了确认壳寡糖和溶剂在Vero E6细胞中的毒性,使用4种浓度的壳寡糖和溶剂处理Vero E6细胞,24小时后,利用相差显微镜以20×10的倍率进行观察。在处理Vero E6细胞24小时后拍摄相差显微镜(LionHeart FX automated Microscop)照片。
其结果如图1所示。
如图1所示,确认用作溶剂的0.1N的盐酸(HCl,Hydrochloric acid)和二甲基亚砜(DMSO,Dimethyl sulfoxide)没有细胞毒性,当为了确认是否具有细胞毒性而使用1%的聚乙二醇辛基苯基醚(TritonX-100)等时,确认到具有细胞毒性。未在壳寡糖中观察到细胞毒性。
2.严重急性呼吸综合征冠状病毒2的细胞凋亡效果评估及病毒选定
使6种严重急性呼吸综合征冠状病毒2(NCCP 43326、NCCP 43327、NCCP 43328、NCCP 43329、NCCP 43330、NCCP 43331)分别感染Vero E6细胞后,观察致细胞病变效应(CPE,Cytopathic effect)。为了了解感染严重急性呼吸综合征冠状病毒2后的Vero E6细胞状态,观察96小时。作为Vero E6细胞感染实验的实验对照组使用2%FBS DMEM。在处理Vero E6细胞96小时后,拍摄相差显微镜照片。
其结果如图2所示。
如图2所示,感染6种严重急性呼吸综合征冠状病毒2后,在所有Vero E6细胞中均观察到细胞凋亡。其中,在感染SARS-CoV-2 NCCP43326的Vero E6细胞中均观察到细胞凋亡和变性。只有在细胞发生变性时才会形成菌斑(plaque)并进行实验,因此,在用于实验的6种严重急性呼吸综合征冠状病毒2中选择确认到细胞变性的NCCP 43326并将其用于下述抗病毒效果测定实验。
3.按照壳寡糖的分子量准备实验物质
为了确认壳寡糖根据分子量的对于严重急性呼吸综合征冠状病毒2的凋亡效果或增殖抑制效果,通过表1所示的多种分子量的壳寡糖进行实验。
表1
序号 | 代号 | 试样名称 | 平均分子量(Da) | 溶剂 |
1 | AG-01 | 壳寡糖2K | 2kDa | 0.1N的盐酸 |
2 | AG-02 | 壳寡糖10K | 10kDa | 0.1N的盐酸 |
3 | AG-03 | 壳寡糖30K | 30kDa | 0.1N的盐酸 |
4 | AG-04 | 壳寡糖50K | 50kDa | 0.1N的盐酸 |
4.壳寡糖根据分子量的对于严重急性呼吸综合征冠状病毒2的抗病毒效果
为了确认抗-严重急性呼吸综合征冠状病毒2效果(定量基因扩增荧光检测(qPCRassay)),在25μg/mL的浓度中,将4种候选物质(AG-01、AG-02、AG-03、AG-04)和对照组(0.1N的盐酸)与严重急性呼吸综合征冠状病毒2(MOI0.01)反应1小时后,感染Vero76细胞(5.0*105细胞/孔接种,6孔板)。通过每15分钟的晃动来使得Vero76细胞感染病毒1小时,随后,去除未感染到细胞的病毒并利用磷酸盐缓冲液(PBS)清洗细胞3次。添加包含各种候选物质的培养基后,在37℃的温度条件下,利用CO2培养箱培养2天。利用 Viral RNA kit从各个实验组的病毒培养液中提取viral RNA,并利用iScript cDNA synthesis kit合成cDNA后,针对严重急性呼吸综合征冠状病毒2的Rdrp、E、N基因进行定量基因扩增荧光检测(qPCR)来定量基因的Ct值。反复进行3次实验后,取结果的平均值来表示对照组的相对值。
其结果如图3所示。
如图3所示,经确认,用于实验的候选物质中的AG-03对于严重急性呼吸综合征冠状病毒2表现出非常高的抗病毒效果。
严重急性呼吸综合征冠状病毒2的基因组组织基因组编码ORF1a及ORF1b两个大基因,上述ORF1a及ORF1b编码16个非结构蛋白(NSP1~NSP16)。这种NSP为形成有关基因组转录及复制的复制转录复合体(RTC)而被处理,刺突(S)、包膜(E)、膜(M)及核衣壳(N)基因编码结构蛋白,如3-胰凝乳蛋白酶样蛋白酶、木瓜蛋白酶样蛋白酶及RNA依赖性RNA聚合酶等非结构蛋白被ORF区域编码。根据世界卫生组织(WHO)的标准,当确认新型冠状病毒肺炎时,在进行核酸序列分析的同时需通过实时逆转录聚合酶链反应(rRT-PCR)等核酸扩增方法(NAAT)检测病毒RNA的固有序列,因此,成为对象的病毒基因包括N、E、S及RdRP基因。
用于实验的三种基因(Rdrp、E、N gene)用作检测严重急性呼吸综合征冠状病毒2的代表检测基因,严重急性呼吸综合征冠状病毒2RNA依赖性RNA聚合酶(ORF1ab)基因为编码(encoding)RNA依赖性聚合酶(RNA-dependent polymerase)的基因,起到复制病毒基因组的作用,是在检测严重急性呼吸综合征冠状病毒2基因组的分子检测中以最优先顺序选择的基因,严重急性呼吸综合征冠状病毒2包膜基因(SARS-CoV-2E gene)为编码病毒包膜蛋白(Envelope protein)的基因,表达构成病毒表面的结构蛋白,属于在严重急性呼吸综合征冠状病毒2基因组检测中额外使用的基因之一。严重急性呼吸综合征冠状病毒2核衣壳基因(SARS-CoV-2N gene)为编码核衣壳蛋白(Nucleocapsid phosphoprotein)的基因,与病毒基因组相结合并表达支持基因组稳定性的蛋白质。
5.壳寡糖对于人冠状病毒229E病毒的抗病毒效果比较
为了确认在上述实验中针对严重急性呼吸综合征冠状病毒2表现出最优秀的抗病毒效果的AG-03壳寡糖是否也对其他冠状病毒也有抗病毒效果,确认了针对作为感染人类的人类甲型冠状病毒(Human alphacoronavirus)的人冠状病毒229E的抗病毒效果。
具体地,在25μg/mL的浓度中,将AG-03和溶剂对照组(0.1N的盐酸)与人冠状病毒229E(MOI 0.01,TCID 50标准)反应1小时后,向MRC-5细胞(5.0*105细胞/孔接种,6孔)感染病毒。通过每15分钟的晃动来使得MRC-5细胞感染病毒1小时,随后,去除未感染到细胞的病毒并利用磷酸盐缓冲液(PBS)清洗细胞3次。添加未包含AG-03的培养基后,在37℃的温度条件下,利用CO2培养箱培养3天。利用 Viral RNA kit从各个实验组的病毒培养液中提取viral RNA并利用iScript cDNA synthesis kit合成cDNA后,针对人冠状病毒229E的Rdrp、E、N基因进行定量基因扩增荧光检测(qPCR)来定量基因的Ct值。为了比较相同浓度中的抗病毒效果,反复进行3次实验后,取结果的平均值来表示对照组的相对值,从而比较对于严重急性呼吸综合征冠状病毒2和人冠状病毒229E的抗病毒效果。
其结果如图4所示。
如图4所示,虽然AG-03对于人冠状病毒229E(HCoV-229E)也表现出抗病毒活性,但是,相比于严重急性呼吸综合征冠状病毒2的抗病毒活性,效果显著降低。
在检测基因中,人冠状病毒229E复制酶多蛋白1ab(HCoV-229E RP1ab)(HCoV229Egp1)基因为编码复制酶多蛋白1ab(Replicase polyprotein 1ab)的基因,表达用于复制病毒基因组的蛋白质。人冠状病毒229E核衣壳基因为编码核衣壳蛋白(Nucleocapsid protein)的基因,表达与病毒基因组结合的蛋白质,人冠状病毒229E刺突基因为编码表面糖蛋白(Surface glycoprotein)(刺突蛋白(Spike glycoprotein))的基因,表达与宿主细胞相互作用的病毒表面蛋白。以上多种基因可作为检测人冠状病毒229E的分子检测目标。
6.壳寡糖对于严重急性呼吸综合征冠状病毒2的增殖抑制效果(Plaque assay)
将200μg/mL的AG-03和对照物质0.1N的盐酸与严重急性呼吸综合征冠状病毒2(500PFU(噬菌斑形成单位)/ml)反应1小时后,感染Vero76细胞(8.0*105细胞/孔接种,6孔板)。通过每15分钟的晃动来使得Vero76细胞感染病毒1小时,随后,去除未感染到细胞的病毒并利用磷酸盐缓冲液(PBS)清洗细胞3次。添加包含1%的低熔点琼脂(low-meltingpoint agar)和200μg/mL候选物质的培养基后,在37℃的温度条件下,利用CO2培养箱培养3天并观察。培养3天后,利用3.7%甲醛(formaldehyde)固定细胞并去除固体琼脂层(solid-agar layer)后,利用0.5%结晶紫染色液(crystal violet)对细胞染色15分钟并利用磷酸盐缓冲液(PBS)脱色2次后观察是否形成菌斑(plaque)。为了确认对于严重急性呼吸综合征冠状病毒2的增殖抑制效果,定量菌斑数量(噬菌斑形成单位/ml)。为了在相同浓度中比较抗病毒效果而反复进行2次实验后,取结果的平均值来表示对照组的相对值。
其结果如图5所示。
如图5所示,根据抗-严重急性呼吸综合征冠状病毒2效果的定量结果,AG-03物质对于严重急性呼吸综合征冠状病毒2的表达率为61.7%,相比于对照组,针对病毒增殖的抑制效果为38.3%。
7.壳聚糖对于严重急性呼吸综合征冠状病毒2的抗病毒效果定量
壳聚糖通过对甲壳素进行脱乙酰化的工序生成。在90℃的温度条件下加热50%氢氧化钠(NaOH)并加入甲壳素反应15小时。进行水洗后,加入5L的氧化氢(H2O2)反应15小时。进行水洗、除湿工序后,均匀铺在干燥机中,并在60℃的温度条件下干燥8小时以上,随后,通过粗粉碎/微粉碎来使得Amicogen公司生产220kDa的壳聚糖(批号3241190)。
将50μg/ml与严重急性呼吸综合征冠状病毒2反应1小时后,感染Vero细胞(MOI0.01,TCID 50标准)。感染Vero细胞后,每15分钟进行晃动并去除病毒后,利用磷酸盐缓冲液(PBS)清洗细胞3次。感染严重急性呼吸综合征冠状病毒2的Vero细胞更换一次新培养基后进行培养。利用严重急性呼吸综合征冠状病毒2感染Vero细胞并经过2天后,提取RNA并使用SD Biosensor公司销售的新型冠状病毒肺炎试剂(Standard M Corona 19RapidDiagnostic Kit,STANDARD M n-Cov Real-Time Detection kit)进行实时聚合酶链式反应(real-time PCR)。以干涉病毒合成的RdRp基因和干涉包膜(Envelope)的E基因为目标,定量其基因的Ct值。
其结果如图6所示。
如图6所示,根据利用SD Biosensor公司的新型冠状病毒肺炎试剂定量的结果,在壳聚糖中检测到干涉病毒表达的RdRp基因和E基因,相比于溶剂对照组,并未表现出病毒抑制活性。
产业上的可利用性
本发明的包含特定分子量范围的低分子壳聚糖或壳寡糖的组合物抑制严重急性呼吸综合征冠状病毒2的翻译、复制、增殖,并且,可有效预防或治疗因严重急性呼吸综合征冠状病毒2感染引起的COVID-19感染疾病,因此,产业上的可利用性非常高。
Claims (4)
1.低分子量壳聚糖或壳寡糖在制备用于治疗严重急性呼吸综合征冠状病毒2感染的药剂中的用途,其中所述低分子量壳聚糖或壳寡糖的平均分子量为25000Da至35000Da。
2.低分子量壳聚糖或壳寡糖在制备用于严重急性呼吸综合征冠状病毒2的抗病毒剂中的用途,其中所述低分子量壳聚糖或壳寡糖的平均分子量为25000Da至35000Da。
3.根据权利要求2所述的用途,其中所述抗病毒剂为化妆品组合物或准药品组合物。
4.根据权利要求2所述的用途,其中所述抗病毒剂为皮肤外用剂组合物。
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