CN114601820A - 菊苣酸在治疗SARS-CoV-2感染中的应用 - Google Patents
菊苣酸在治疗SARS-CoV-2感染中的应用 Download PDFInfo
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- CN114601820A CN114601820A CN202011425593.8A CN202011425593A CN114601820A CN 114601820 A CN114601820 A CN 114601820A CN 202011425593 A CN202011425593 A CN 202011425593A CN 114601820 A CN114601820 A CN 114601820A
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Abstract
本发明涉及菊苣酸、其可药用的盐或含有菊苣酸天然植物在制备预防、治疗与血管紧张素转化酶2(ACE2)相关的疾病中的用途。具体而言，本发明涉及一种通式(I)所示的菊苣酸或其可药用的盐在制备预防、治疗ACE2相关的疾病，特别是预防、治疗新型冠状病毒性肺炎(COVID‑19)的药物中的用途。
Description
技术领域
本发明涉及菊苣酸、其可药用的盐在制备预防、治疗血管紧张素转化酶2(ACE2)相关的疾病中的用途。具体而言，本发明涉及一种通式(I)所示的菊苣酸或其可药用的盐在制备预防、治疗ACE2相关的疾病，特别是预防、治疗新型冠状病毒性肺炎(COVID-19)的药物中的用途。
背景技术
新型冠状肺炎病毒(SARS-CoV-2)导致的COVID-19全球已有超6000万人确诊，超过两百万人死亡，目前尚无有效控制感染与传播、治疗的药物。血管紧张素转化酶2(ACE2)是SARS-CoV-2进入宿主细胞的主要受体；宿主细胞ACE2的表达量决定了细胞对SARS-CoV-2感染的易感性。
菊苣酸，别名二咖啡因基酒石酸，是咖啡酸和酒石酸的缩合酯化产物，含有两个手性中心，存在三种立体异构体：R，R-菊苣酸，S，S-菊苣酸和R，S-菊苣酸。
菊苣酸最早分离自菊苣，广泛存在于紫锥菊，白头翁，蒲公英叶，罗勒，柠檬香和水生植物(海藻和海草)中。体外和体内研究表明，菊苣酸可以刺激吞噬作用，抑制透明质酸酶的功能，保护胶原蛋白免受可导致降解自由基的损伤，即具有抗自由基氧化作用。同时菊苣酸还是HIV-1整合酶抑制剂，具有抗HIV病毒活性(EC50 1.7-20μm，IC50 40-60μm)。此外，菊苣酸还具有抗菌，抗炎，提高免疫力，降血糖，保护肝脏，降尿酸以及抗动脉粥样硬化等作用。
ACE2是新型冠状病毒进入人体细胞的关键受体，通过抑制ACE2蛋白的表达，可以显著降低感染新型冠状病毒的风险，缓解疾病进展。目前严重急性呼吸系统综合征2型冠状病毒感染尚未有疗效明确的治疗药物，临床治疗多采取隔离、抗病毒、对症支持等疗法为主，然而这些治疗仍不能满足临床需求。因此开展针对SARS-CoV-2的靶向药物研究将具有重大意义。
在前期筛选试验当中发现，菊苣酸在ACE2基因启动子报告基因筛选模型中具有较好抑制活性，因此，菊苣酸及其结构类似物在抑制ACE2表达，防控和治疗新型冠状病毒领域具有广泛研究及应用前景。
发明内容
为解决现有技术中存在的缺点和不足，本发明提供了一种通式(I)所示的菊苣酸、其可药用的盐或含有菊苣酸天然植物，在如下(1)-3)中任一种应用：
其中所述的应用为：
(1)制备用于预防、缓解或治疗SARS-CoV-2或其同源变异病毒所引起的疾病的药物；
(2)制备用于预防、缓解或治疗SARS-CoV-2或其同源变异病毒感染的药物；
(3)制备作为ACE2抑制剂的药物。
其中所述含有菊苣酸天然植物包括紫锥菊，白头翁，蒲公英叶，罗勒，柠檬香和水生植物，其中所述的水生植物优选为海藻和海草。
其中所述感染包括肺炎、急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克；其中所述疾病包括呼吸系统疾病或COVID-19。
所述疾病症状包括发热、咳嗽、咽痛、肺炎、急性呼吸道感染、严重急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克等感染。
所述疾病包括呼吸系统疾病或COVID-19。
所述SARS-CoV-2或其同源变异病毒所引起的疾病包括：SARS-CoV-2或其同源变异病毒无症状感染、SARS-CoV-2或其同源变异病毒轻度感染、SARS-CoV-2或其同源变异病毒中度感染或SARS-CoV-2或其同源变异病毒重度感染。
所述COVID-19的症状包括：无症状、无明显症状、轻度至中度的呼吸道症状、严重呼吸综合征、急性呼吸窘迫综合征、脓毒症、肾功能衰竭、难以纠正的代谢性酸中毒或出血凝血障碍；所述严重呼吸综合征包括发热、干咳、乏力、气喘和/或呼吸乏力等症状。
经申请人研究发现，化合物菊苣酸出乎意料地能对SARS-CoV-2病毒的受体ACE2的表达产生强抑制作用，且其毒性低，安全性好，毒副作用低，能作为临床上预防、缓解和/或治疗COVID-19/SARS-CoV-2的药物。
本发明提供一种药物组合物，所述组合物包含通式(I)所述菊苣酸和药学上可接受的载体或辅料。
另一方面，本发明提供菊苣酸的制剂，所述的药物制剂包括固体制剂、注射剂、半固体制剂、液体制剂。
本发明提供菊苣酸的制剂，所述的药物制剂还包括胶囊、片剂、丸剂、霜剂、乳剂、软膏剂、混悬剂、冻干剂、胶囊、缓释剂、颗粒剂、冲剂、注射药剂或喷剂。
本发明还提供一种联合治疗药物组合，所述药物包括菊苣酸与至少一种其他预防、缓解或治疗COVID-19肺炎或其同源变异病毒肺炎的药物、抗体或疫苗。所述的其他预防、缓解或治疗COVID-19肺炎或其同源变异病毒肺炎的药物、抗体或疫苗包括含中药成分和/或西药成分的组合物；所述的中药成分和/或西药成分包括：阿匹莫德(apilimod)、R82913(CAS号：126347-69-1)、DS-6930(CAS号：1242328-82-0)、ONO 5334(CAS号：868273-90-9)、瑞德西韦、磷酸奥司他韦(Oseltamivir phosphate)、汉防己甲素(HanfangchinA)、氯法齐明(clofazamine)、阿司咪唑(astemizole)、重组人源血管紧缩素转换酶2(rhACE2)或法匹拉韦(Favipiravir)和/或它们的药学上可接受的盐等可以预防、缓解和/或治疗SARS-CoV-2或其同源变异病毒所引起的疾病的化合物。
所述联合治疗药物组合能有效抑制SARS-CoV-2感染及其在细胞内的增殖，其疗效好，毒副作用低，能降低病毒的耐药性，具有显著的协同增效作用。
本发明提供一种体外调节ACE2的方法，该方法包括报告基因模型、肺癌细胞模型或动物组织模型，其中所述的方法包括ACE2与权利要求1中的化合物相接触。
相比现有技术，本发明具有以下技术效果：
(1)能有效抑制冠状病毒SARS-CoV-2进入细胞及在细胞内的复制和/或增殖；
(2)能有效抑制SARS-CoV-2或其同源变异病毒的复制或增殖及其所产生的细胞病变效应；
(3)其毒性极低，安全性高；
(4)能降低病毒耐药性，降低药物毒副作用等；
(5)结构简单，有利于合成、生产和分销。
详细说明
本发明所述基团和化合物中所涉及的元素碳、氢、氧、氮或卤素均包括它们的同位素情形，本发明所述基团和化合物中所涉及的元素碳、氢、氧或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物，其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的药物。本发明的前药通过修饰雌二醇中的功能基团来制备，该修饰可以通过常规的操作或者在体内被除去，而得到雌二醇。
“有效剂量”指引起组织、系统或受试者生理或医学反应的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。
“Relative expression”是指相对表达量。
“Vehicle”是指溶媒。
附图说明
图1为测试例3中菊苣酸抑制小鼠肺组织ACE2蛋白表达的活性测试图
具体实施方式
测试例1抑制ACE2基因表达的化合物筛选
连续传代的293T细胞铺板于96孔培养板，每孔1×104细胞；受试化合物溶于DMSO中，以完全培养基稀释后加至培养孔，终浓度2μM，设置双复孔，DMSO同比稀释作为空白对照，孵育1小时后以PEI转染报告基因质粒pGL3-ACE2(50ng/孔)和海肾荧光素酶(Renilla)报告基因质粒pRL-SV40(10ng/孔)。pRL-SV40质粒表达海肾红色荧光素酶，作为pGL3-ACE2质粒转染细胞效率标准化的参照，消除因瞬时转染效率差别导致各空间萤火虫荧光素酶活性的差异。转染72小时后，以Dual-Glo Luciferase Assay System(Promega)检测细胞中萤火虫荧光素酶和海肾荧光素酶的活性；以萤火虫荧光素酶信号/海肾荧光素酶信号比值作为相对报告基因信号，并与空白对照组相比，获得化合物抑制ACE2启动子活性的百分数。
筛选化合物在2μM浓度时对细胞的毒性以CellTiter-Glo(Promega)测定。
结论：菊苣酸在ACE2基因启动子报告基因筛选模型中具有较好抑制活性，2μM浓度下抑制率可达83％。
测试例2抑制细胞ACE2蛋白表达的活性测试
连续传代培养人肺癌细胞A549以菊苣酸(终浓度2μM)处理72小时后，收集细胞，在含有SDS、蛋白酶抑制剂的裂解液中裂解后，BCA法测定蛋白浓度，SDS-PAGE分离后以Western Blotting检测细胞中ACE2蛋白表达量，并以GAPDH为内参进行半定量分析。
结果显示，2μM菊苣酸可降低细胞内ACE2蛋白的表达50％以上。
测试例3抑制小鼠肺组织ACE2蛋白表达的活性测试
菊苣酸溶于DMSO+HS-15+0.9％NS(5:5:90，v/v/v)，按30mg/kg灌胃給予雄性成年ICR小鼠，每天一次，连续给药7天。最后一次给药后4小时处死动物，迅速采集肺组织，液氮速冻，然后于含蛋白酶抑制剂的裂解液中匀浆提取总蛋白，BCA法测定蛋白浓度，WesternBlotting检测组织中ACE2蛋白表达水平，并以GAPDH为內标半定量分析。
根据图1结果显示，菊苣酸连续给药可降低小鼠肺组织中ACE2蛋白表达水平30％。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
1.一种通式(I)所示的菊苣酸、其可药用的盐或含有菊苣酸天然植物在如下(1)-3)中任一种应用：
(1)制备用于预防、缓解或治疗SARS-CoV-2及其他以ACE2为受体的病毒或其同源变异病毒所引起的疾病的药物；
(2)制备用于预防、缓解或治疗SARS-CoV-2及其他以ACE2为受体的病毒或其同源变异病毒感染的药物；
(3)制备作为ACE2抑制剂的药物；
2.根据权利要求1所述的用途，所述感染包括肺炎、急性呼吸道感染、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症或脓毒性休克。
3.根据权利要求1所述的用途，所述疾病包括呼吸系统疾病或COVID-19。
4.根据权利要求1所述的用途，所述药物为组合物，所述组合物包含通式(I)所述菊苣酸和药学上可接受的载体或辅料。
5.根据权利要求1所述的用途，所述药物包括固体制剂、注射剂、半固体制剂、液体制剂。
6.根据权利要求1所述的用途，所述药物包括胶囊、片剂、丸剂、霜剂、乳剂、软膏剂、混悬剂、冻干剂、胶囊、缓释剂、颗粒剂、冲剂、注射药剂或喷剂。
7.根据权利要求1所述的用途，所述药物还包括至少一种其他预防、缓解或治疗COVID-19肺炎或其同源变异病毒肺炎的药物、抗体或疫苗。
8.根据权利要求1所述的用途，所述的含有菊苣酸天然植物包括紫锥菊，白头翁，蒲公英叶，罗勒，柠檬香和水生植物，其中所述的水生植物优选为海藻和海草。
9.一种体外调节ACE2的方法，该方法包括报告基因模型、肺癌细胞模型或动物组织模型，其中所述的方法包括ACE2与权利要求1中的化合物相接触。
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