CN114751914A - 一种倍半萜类衍生物及其在制备广谱抗病毒药物中的应用 - Google Patents
一种倍半萜类衍生物及其在制备广谱抗病毒药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种倍半萜类衍生物及其在制备广谱抗病毒药物中的应用，所述倍半萜类衍生物具有激动异质性胞核核糖核蛋白A2/B1，激活TANK结合激酶1‑干扰素调节因子3细胞信号通路，增加内源性I型干扰素的分泌，对多种病毒有抑制作用，可作为广谱抗病毒药物，预防或治疗多种病毒感染性疾病和病症，包括新冠病毒、水疱性口炎病毒VSV‑G、艾滋病病毒、丙型肝炎病毒、乙型脑炎病毒、流感病毒、脊髓灰质炎病毒、柯萨奇病毒、登革热病毒、轮状病毒、烟草花叶病毒、麻疹病毒、腮腺炎病毒、埃博拉病毒、马尔堡病毒、泡疹病毒和腺病毒。以倍半萜类衍生物为原料可制备成片剂、胶囊、滴丸等口服剂型或吸入剂、注射剂等临床上可接受的药物制剂。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种有益于治疗广谱病毒感染性疾病和病症的倍半萜类衍生物及其应用。
背景技术
病毒感染一直持续地威胁着人类的生命健康，特异性疫苗、抗病毒药物在取得治疗效果的同时，仍然存在毒性、耐药性或是疫苗只能预防不能起到治疗作用等问题。此外，一些急性突发性病毒感染性疾病的爆发，没有广谱的抗病毒药物可以救治，如新型冠状病毒肺炎严重危害人类健康，对社会公共卫生安全产生极大的威胁。目前，在急性病毒爆发事件中，干扰素、激素疗法取得一定治疗效果的同时，脱靶、副作用问题依然存在。因此，发现广谱抗病毒药物是解决副作用和耐药性问题、急性病毒爆发问题的关键。
调节宿主免疫是广谱抗病毒药物的研究策略。免疫应答功能障碍被认为是病毒持续感染的主要原因，因此恢复或增强固有免疫，诱导病毒适应性免疫应答，可能有助于清除病毒。目前为止，基于免疫策略的尝试并不理想，而且存在脱靶、副作用显著等风险。因此，有效的抗病毒和免疫治疗相结合的方法是广谱抗病毒的新策略。
发明内容
本发明的目的在于针对现有技术的不足，提供一种倍半萜类衍生物及其在制备广谱抗病毒药物中的应用。本发明能显著抑制新冠病毒(SARS-CoV-2)、水疱性口炎病毒VSV-G、艾滋病病毒、丙型肝炎病毒、乙型脑炎病毒、流感病毒、脊髓灰质炎病毒、柯萨奇病毒、登革热病毒、轮状病毒、烟草花叶病毒、麻疹病毒、腮腺炎病毒、埃博拉病毒、马尔堡病毒、泡疹病毒和腺病毒等RNA和DNA病毒，是具有新靶点的有效的广谱抗病毒药物。
为了实现本发明的上述目的，本发明提供了如下的技术方案：一种倍半萜类衍生物，它具有以下结构式I、II、III或IV所示结构：
其中，结构式(I)～(IV)中，R1各自独立地选自苯甲酸酯基、对羟基苯甲酸酯基、多羟基苯甲酸酯基、对甲氧基苯甲酸酯基、多甲氧基苯甲酸酯基，氟、氯、溴取代的苯甲酸酯基、氢。
进一步地，优选具有结构式I所示结构，R1优选为苯甲酸酯基或对羟基苯甲酸酯基。
本发明还提供了一种上述倍半萜类衍生物在制备治疗病毒感染疾病的药物中的应用。
进一步地，所述病毒感染疾病新冠病毒(SARS-CoV-2)、水疱性口炎病毒VSV-G、艾滋病病毒、丙型肝炎病毒、乙型脑炎病毒、流感病毒、脊髓灰质炎病毒、柯萨奇病毒、登革热病毒、轮状病毒、烟草花叶病毒、麻疹病毒、腮腺炎病毒、埃博拉病毒、马尔堡病毒、泡疹病毒和腺病毒导致的病毒感染疾病。
进一步地，所述倍半萜类衍生物可与药用载体和/或食用载体组合。
进一步地，所述倍半萜类衍生物以治疗有效剂量包含于所述药物中。
进一步地，所述治疗有效剂量足够激动hnRNPA2B1，激活TANK结合激酶1-干扰素调节因子3(TBK1-IRF3)途径，导致内源性I型干扰素的产生。
进一步地，所述药物包括口服制剂和非口服给药制剂；所述口服制剂包括片剂、丸剂、胶囊剂、颗粒剂、微囊片剂、混悬剂、滴丸、口服液体；所述非口服给药制剂包括注射剂、气雾剂、栓剂、皮下给药剂型。
本发明的有益效果是，本发明能够激动hnRNPA2B1，形成同源二聚体，激活TANK结合激酶1-干扰素调节因子3(TBK1-IRF3)途径，导致内源性I型干扰素的产生，具有显著病毒活性。与目前治疗病毒感染的药物相比，本发明具有全新的靶点，能提高/改善毒理学安全性(即毒性降低)、提高/改善代谢稳定，本发明还具有较长的半衰期和/或较小的副作用，同时产生类似或提高的生物活性(药效)。本发明可用于预防或治疗病毒感染疾病和病症以及用作内脏损伤的保护剂，如乙肝病毒引起的肝脏损伤。此外，也可用于研究与hnRNPA2B1相关的病毒感染的化学工具药物。
本发明能有效抑制：新冠病毒(SARS-CoV-2)(半数有效量IC50 485nM)、水疱性口炎病毒(IC50 1.72μM)；艾滋病病毒(IC50 1.70μM)、丙型肝炎病毒(IC50 551nM)、乙型脑炎病毒(IC50 1.31μM)、流感病毒(IC50 720nM)、脊髓灰质炎病毒(IC50 2.75μM)、柯萨奇病毒(IC50720nM)、登革热病毒(IC50 314nM)、轮状病毒(IC50 541nM)、烟草花叶病毒(IC501.45μM)、麻疹病毒(IC50 1.62μM)、腮腺炎病毒(IC50 1.81μM)(IC50 1.37μM)、埃博拉病毒(IC50 1.41μM)、马尔堡病毒(IC50 1.38μM)、泡疹病毒(IC50 1.79μM)和腺病毒(IC50 1.48μM)，远远强于阳性对照，且在500μM高浓度下不显示细胞毒性；进一步研究显示，小鼠体内水平半数有效量为20mg/kg，小鼠单日单次最大给药剂量2000mg/kg，连续观察7天，未出现毒性反应。表明该药物为高效低毒的抑制多种病毒。可作为广谱抗病毒药物。
附图说明
图1是西印度醋栗戊烷酰胺PA-X1在细胞模型中的病毒抑制活性示意图，其中，(a)为对新冠病毒(SARS-COV-2)抑制活性示意图，(b)为对水疱性口炎病毒抑制活性示意图；
图2是西印度醋栗戊烷酰胺PA-X1上调内源性I型干扰素IFN-β示意图；
图3西印度醋栗戊烷酰胺PA-X1与hnRNPA2B1结合模式图。
具体实施方式
经研究发现，激动hnRNPA2B1，激活TANK结合激酶1-干扰素调节因子3(TBK1-IRF3)途径，导致内源性I型干扰素的产生，对多种病毒具有显著抑制活性。因此，患有这种疾病的个体可接受含有本发明中涉及的西印度醋栗戊烷酯或酰胺(或作为主要活性成分之一的在结构上与西印度醋栗戊烷酯或酰胺相关的类似物及同类物之一)的组合物。
此外，研究hnRNPA2B1是探讨病毒感染疾病，如新冠病毒(SARS-COV-2)、水疱性口炎病毒、乙肝病毒、丙肝病毒，以及病毒所致的内脏损伤等疾病发病机制的重要手段。本发明中涉及的西印度醋栗戊烷酯或酰胺可以显著上调内源性I型干扰素IFN-β。因此，本发明中涉及的西印度醋栗戊烷酯或酰胺(或作为主要活性成分之一的在结构上与西印度醋栗戊烷酯或酰胺相关的类似物及同类物之一)可用于探讨病毒感染疾病发病机理的研究。
本发明的西印度醋栗戊烷酯或酰胺具有8个手性立体中心，因此，西印度醋栗戊烷酯或酰胺可作为外消旋(或非对映异构体)混合物、R和S对映体(或非对映体)混合物或纯对映体(R或S)(或非对映体)而证实具有更好的生物活性。当一种纯对映体显示出更好的生物活性时，即为优对映体(eutomer)，而生物活性较低的该对映体称为劣对映体(distomer)。
本发明的西印度醋栗戊烷酯或酰胺具有3个游离羟基，因此，西印度醋栗戊烷酯或酰胺可作为盐和/或酯而证实具有更好的生物活性和/或更优的代谢参数。
本发明的有效药物制剂和组合物可用来治疗多种病毒感染疾病，如新冠病毒(SARS-CoV-2)、水疱性口炎病毒VSV-G、艾滋病病毒、丙型肝炎病毒、乙型脑炎病毒、流感病毒、脊髓灰质炎病毒、柯萨奇病毒、登革热病毒、轮状病毒、烟草花叶病毒、麻疹病毒、腮腺炎病毒、埃博拉病毒、马尔堡病毒、泡疹病毒和腺病毒等病毒感染疾病和病症。虽然这些药物制备通常用于人患者的治疗，但它们也可以用于治疗其他动物的相似或相同的疾病，所述其他动物例如灵长类动物、家禽(如鸡、鸭、鹅))、农场动物(如猪、牛)、体育用动物(如赛马)和宠物(如狗和猫)。
本发明所述可药用载体包括但不限于碳酸钙、磷酸钙、硫酸钙、蔗糖、葡萄糖、乳糖、果糖、木糖醇、山梨醇、淀粉、淀粉糊、纤维素衍生物、明胶、聚乙烯吡咯烷酮、氯化钠、糊精、硬脂酸、硬脂酸镁、硬脂酸钙、植物油、聚乙二醇、无菌磷酸盐缓冲盐水、盐水、林格氏溶液以及它们的组合。
本发明所述可药用盐类包括钠盐、钾盐、锂盐、锌盐、铝盐、钙盐和镁盐。
本发明的所述口服剂型包括但不局限于固体口服剂型(如肠溶衣片、滴丸、口服片、咀嚼片、颗粒剂、粉末或胶囊)或液体口服剂型(如糖浆或酊剂)。此外，本发明中的西印度醋栗戊烷酯或酰胺及其衍生物或组合物还可以添加到食物和饮料中，用于口服施用。此外，本发明中的西印度醋栗戊烷酯或酰胺及其衍生物或组合物也可以配制成口香糖，以促进口服递送和吸收。
本发明所述的非口服剂型包括但不局限于通过注射或其他全身途径给药，所述其它全身途径例如经皮施用或经粘膜施用(例如经鼻、舌下、口含、经阴道或直肠，通过栓剂)。其他施用途径(例如可在兽医应用中使用的)包括肠内和胃肠外递送，包括肌肉、皮下和/或髓内注射，以及鞘内注射、直接脑室注射、静脉内注射、腹膜内注射、鼻内注射或眼球内注射。
本发明涉及的西印度醋栗戊烷酯或酰胺及其衍生物或组合也可与其他药物活性成分联用，以制备其他的新药物组合物。
本发明的西印度醋栗戊烷酯或酰胺或其任意衍生物或其组合用以缓解上述症状的证实性疗效和治疗相关活性。
上述本发明西印度醋栗戊烷酯或酰胺或其任意衍生物或其组合的治疗作用、良好的药物代谢参数和通常无毒性使得本发明化合物成为用于治疗上述病症的理想药物。
本发明倍半萜类衍生物的结构式如下所示：
所述倍半萜类衍生物的制备包括如下步骤：
1、10kg西印度醋栗(Phyllanthus acidus)的根茎经甲醇回流提取三次得浸膏429g，粗提物用5.5L H2O分散，分别用等体积的乙酸乙酯和正丁醇萃取5次，正丁醇萃取层浓缩至干，甲醇溶解，大孔树脂柱Diaion HP20SS柱层析，用CH3OH/H2O(0-100)(V/V％)洗脱，得到5个部分。合并2和3部分，经Sephadex LH20(CH3OH 0-100％)柱层析得到5个部分。合并前两个部分(41.0g)再经正相硅胶柱层析(CHCl3-CH3OH-H2O，9:1:0-7:3:0.5)、反相RP-8(CH3OH 30％-80％)和凝胶树脂柱Toyopearl HW 40C(CH3OH 0-30％)柱反复柱层析以及制备高效液相色谱(CH3CN 15％-30％)得到西印度醋栗酸苷A(phyllanthacidoid A)(10g)和B(phyllanthacidoid B)(1g)。
2、西印度醋栗酸苷A和B(1.27*10-5mol)分别溶于1ml的0.72M碳酸钾水溶液中，60℃温度下水解两个小时生成西印度醋栗酸苷苷元A和B。
3、将西印度醋栗酸苷苷元A溶于有机溶剂，常温下与20倍摩尔当量的正戊胺反应12小时生成化合物PA-X1。
4、将西印度醋栗酸苷苷元B溶于有机溶剂，常温下与20倍摩尔当量正戊胺反应12小时生成化合物PA-X2。
5、将西印度醋栗酸苷苷元A溶于有机溶剂，常温下与367倍摩尔当量正戊醇反应12小时生成化合物PA-X3。
6、将西印度醋栗酸苷苷元B于有机溶剂，常温下与367倍摩尔当量正戊醇反应12小时生成化合物PA-X4。
7、将西印度醋栗酸苷苷元A溶于有机溶剂，常温下与20倍摩尔当量的丁胺反应12小时生成化合物PA-X5。
8、将西印度醋栗酸苷苷元B溶于有机溶剂，常温下与20倍摩尔当量正丁胺反应12小时生成化合物PA-X6。
9、将西印度醋栗酸苷苷元A溶于有机溶剂，常温下与367倍摩尔当量正丁醇反应12小时生成化合物PA-X7。
10、将西印度醋栗酸苷苷元B于有机溶剂，常温下与367倍摩尔当量正丁醇反应12小时生成化合物PA-X8。
以上步骤中，没有特别说明的比例均为摩尔比。
下面以本发明的实施例来进一步说明本发明的实质性内容，但不以任何方式对本发明加以限制，基于本发明所作的任何变换或替换，均属于本发明的保护范围。
实施例1：PA-X1(PAC5)的合成
步骤(1)：将大约10mg的西印度醋栗酸苷A(phyllanthusol A，PA)置于反应管中，加入1ml的0.72M碳酸钾溶液。溶解后，放入60℃油浴锅，磁力搅拌两个小时，反应至原料消失。用1M的盐酸将溶液中和至酸性，PH值约为2。将溶液加入一定量食盐水至体积约为4.5ml，用4.5×3ml乙酸乙酯萃取，合并有机相，减压蒸馏除掉溶剂，得产物；步骤(2)：取步骤(1)中得到的产物10mg溶解于1ml的3A分子筛干燥后的DMF置于反应管中，加入20倍摩尔当量的正戊胺。然后分别加入10倍摩尔当量HOSU、EDCI以及两倍摩尔当量DMAP，常温下反应过夜，以TLC监测原料反应情况，通常在12小时后反应完毕。反应完毕后，反应液加入10％柠檬酸至4-5ml，用5×3ml乙酸乙酯萃取，合并有机相，浓缩，再用大约7ml的二氯甲烷溶解，如有沉淀可加入极少量甲醇助溶(甲醇含量少于5％)，用氨基硅胶分离纯化，得到PA-X1，产率约为51％。
PA-X1的波谱数据：ESI-MS:m/z 508[M+H]+；1H NMR(600MHz,MeOD)δ7.86(ddd,J＝8.8,2.7,2.0Hz,2H,H-16,H-20),6.73(ddd,J＝8.8,2.7,2.0Hz,2H,H-17,H-19),5.12(brd,J＝2.6Hz,1H,H-10),4.01(t,J＝3.2Hz,1H,H-5),3.93(t,J＝11.4Hz,1H,H-12a),3.79(dd,J＝10.5,5.6Hz,1H,H-1),3.65(s,1H,H-7),3.49(dd,J＝11.1,4.5Hz,1H,H-12b),3.01–2.92(m,2H,H-1'),2.33(ddd,J＝15.1,11.3,5.6Hz,1H,H-3),2.10–2.03(m,1H,H-9a),2.02–1.95(m,2H,H-11,H-9b),1.88(ddd,J＝14.6,11.7,3.2Hz,1H,H-2a),1.69(dt,J＝14.0,5.7Hz,1H,H-4a),1.59(ddd,J＝14.4,5.3,3.5Hz,1H,H-4b),1.46(dt,J＝13.9,9.8Hz,1H,H-2b),1.31(dt,J＝14.8,7.2Hz,2H,H-2'),1.25–1.17(m,2H,H-3'),1.16–1.09(m,2H,H-4'),0.79(t,J＝7.3Hz,3H,H-5'),0.78(d,J＝6.9Hz,3H,H-13)。
实施例2：PA-X2的合成
步骤(1)：将10mg的西印度醋栗酸苷B(phyllanthusol B,PB)置于反应管中，加入1ml的0.72M碳酸钾溶液。溶解后，60℃加热搅拌两个小时，反应至原料消失。用1M的盐酸将溶液中和至酸性，PH值约为2。将溶液加入一定量食盐水至体积约为4.5ml，用4.5×3ml乙酸乙酯萃取，合并有机相，减压蒸馏除掉溶剂后，得产物；步骤(2)：取步骤(1)中得到的产物10mg溶解于1ml的3A分子筛干燥后的DMF置于反应管中，加入20倍摩尔当量的正戊胺。然后分别加入10倍摩尔当量HOSU、EDCI以及两倍摩尔当量DMAP，常温下反应过夜，以TLC监测原料反应情况，通常在12小时后反应完毕。反应完毕后，反应液加入10％柠檬酸至4-5ml，用5×3ml乙酸乙酯萃取，合并有机相，浓缩，再用大约7ml的二氯甲烷溶解，如有沉淀可加入极少量甲醇助溶(甲醇含量少于5％)，用氨基硅胶分离纯化，得到PA-X2，产率约为44％。
PA-X2的波谱数据：ESI-MS:m/z 514[M+Na]+；1H NMR(600MHz,MeOD)δ8.00(brdd,J＝8.3,1.3Hz,2H,H-16,H-20),7.49(brt,J＝7.4Hz,1H,H-18),7.37(brt,J＝7.8Hz,2H,H-17,H-19),5.18(brd,J＝2.6Hz,1H,H-10),4.02(t,J＝3.3Hz,1H,H-5),3.95(t,J＝11.4Hz,1H,H-12a),3.79(dd,J＝10.5,5.5Hz,1H,H-1),3.65(s,1H,H-7),3.51(dd,J＝11.1,4.4Hz,1H,H-12b),3.00–2.89(m,2H,H-1'),2.33(ddd,J＝15.1,11.3,5.6Hz,1H,H-3),2.09(dd,J＝14.8,3.2Hz,1H,H-9a),2.05–1.97(m,2H,H-11,H-9b),1.89(ddd,J＝14.7,11.6,3.3Hz,1H,H-2a),1.68(dt,J＝14.0,5.6Hz,1H,H-4a),1.58(ddd,J＝14.4,5.4,3.6Hz,1H,H-4b),1.47(dt,J＝14.0,9.9Hz,1H,H-2b),1.30(dt,J＝14.4,7.2Hz,2H,H-2'),1.24–1.17(m,2H,H-3'),1.12(tdd,J＝9.6,7.0,3.7Hz,2H,H-4'),0.80(t,J＝7.2Hz,3H,H-5'),0.79(d,J＝7.2Hz,3H,H-13)。
实施例3：PA-X5合成
步骤(1)：将大约10mg的西印度醋栗酸苷A(phyllanthusol A，PA)置于反应管中，加入1ml的0.72M碳酸钾溶液。溶解后，放入60℃油浴锅，磁力搅拌两个小时，反应至原料消失。用1M的盐酸将溶液中和至酸性，PH值约为2。将溶液加入一定量食盐水至体积约为4.5ml，用4.5×3ml乙酸乙酯萃取，合并有机相，减压蒸馏除掉溶剂，得产物；步骤(2)：取步骤(1)中得到的产物10mg溶解于1ml的3A分子筛干燥后的DMF置于反应管中，加入20倍摩尔当量的正丁胺。然后分别加入10倍摩尔当量HOSU、EDCI以及两倍摩尔当量DMAP，常温下反应过夜，以TLC监测原料反应情况，通常在12小时后反应完毕。反应完毕后，反应液加入10％柠檬酸至4-5ml，用5×3ml乙酸乙酯萃取，合并有机相，浓缩，再用大约7ml的二氯甲烷溶解，如有沉淀可加入极少量甲醇助溶(甲醇含量少于5％)，用氨基硅胶分离纯化，得到PA-X5，产率约为49％。
PA-X5的波谱数据：ESI-MS:m/z 516[M+Na]+；1H NMR(600MHz,MeOD)δ7.97(ddd,J＝8.82,2.64,2.04Hz,2H,H-17,H-21),6.84(ddd,J＝8.82,2.70,1.98Hz,2H,H-18,H-20),5.24(br d,J＝2.5Hz,1H,H10),4.12(t,J＝3.2Hz,1H,H-5),4.05(t,J＝11.4Hz,1H,H-12),3.91(dd,J＝10.5,5.6Hz,1H,H-1),3.76(s,1H,H-7),3.61(dd,J＝11.0,4.4Hz,1H,H-12),3.09(br ddd,J＝13.3,7.1,Hz,2H,H-1'),2.44(ddd,J＝15.0,11.3,5.6Hz,1H,H-3),2.21–2.04(m,3H,H-11H-9),2.00(ddd,J＝14.7,9.4,3.2Hz,1H,H-2),1.81(dt,J＝14.0,5.7Hz,1H,H-4),1.70(ddd,J＝14.4,5.3,3.5Hz,1H,H-4),1.58(dt,J＝14.0,9.8Hz,1H,H-2),1.43–1.36(m,2H,H-2'),1.33–1.25(m,2H,H-3'),0.92(t,J＝7.4Hz,3H,H-4'),0.90(d,J＝6.9Hz,3H,H-13).
实施例4：PA-X7的合成
将实施例1中步骤(1)得到的产物(原料PA用量约10mg)溶解于0.5ml的3A分子筛干燥后的DMF置于反应管中，加入367倍摩尔当量的正丁醇，搅拌混合，然后加入十倍摩尔当量EDCI和两倍摩尔当量DMAP，常温下反应过夜，以TLC监测原料反应情况，通常在12小时后反应完毕。反应完毕后，反应液加入10％柠檬酸至4-5ml，用5×3ml乙酸乙酯萃取，合并有机相，浓缩，再用大约7ml的二氯甲烷溶解，如有沉淀可加入极少量甲醇助溶(甲醇含量少于5％)，用氨基硅胶分离纯化，得到产品，产率约为60％采用薄层色谱法对反应进行监测，反应通常在12小时后完成。反应完成后，向反应混合物中添加EtOAc。用氨基硅胶分离纯化，得到纯的目标产物，产率约为49％。
PA-X7的波谱数据：ESI-MS:m/z 517[M+Na]+；PA-X7的波谱数据：ESI-MS:m/z 517[M+Na]+；1H NMR(600MHz,MeOD)δ7.97(br d,J＝8.7Hz,2H,H-17,H-21),6.83(br d,J＝8.7Hz,2H,H-18,H-20),5.22(br d,J＝2.5Hz,1H,H-10),4.11–3.97(m,4H,H-5,H-12,H-1'),3.81(dd,J＝11.0,4.5Hz,1H,H-1),3.81(s,7-H),3.62(dd,J＝11.1,4.6Hz,1H,H-12),2.54(qd,J＝11.3,5.7Hz,1H,H-3),2.17–2.07(m,3H,H11,H-9),2.01–1.91(m,2H,H-2,H-4),1.86(ddd,J＝14.5,11.5,3.1Hz,1H,H-4),1.60–1.55(m,3H,H-2,H-2'),1.39–1.32(m,2H,H-3'),0.95(t,J＝7.41Hz,3H,H-4'),0.91(t,J＝6.93Hz,3H,H-13).
实施例5：抗新冠病毒(SARS-CoV-2)病毒和水疱性口炎病毒(VSV)体外活性测试体外活性测试
把293T/ACE2或Huh-7细胞接种到24孔板中，密度为每孔104个细胞。孵育一夜后，分别加入适量数量的新冠病毒SARS-CoV-2或水疱性口炎病毒VSV-G，感染12小时后，培养液用含有不同浓度测试样品的新培养置换所。传代3天后，细胞用50μL的裂解试剂(普罗米加)裂解15分钟。然后，通过使用协同HTX(美国Bio Tek)在添加荧光酶测定基板(美国普罗米加)时测量发光，对荧光酶活性进行量化，计算测试样品的半数抑制浓度，分别为新冠病毒(SARS-CoV-2)(半数有效量IC50 485nM，如图1(a)所示)和水疱性口炎病毒(IC50 1.72μM，如图1(b)所示)。
实施例6：上调内源性I型干扰素IFN-β抗病毒的作用机制研究
我们研究发现PAC5在hnRNPA2B1的RNA识别基序1(RRM1)中结合Asp49附近的口袋(图2)，激活hnRNPA2B1蛋白，增强TBK1和IRF3的磷酸化，导致TBK1-IRF3途径的启动，激活I型IFN信号通路，显著增加了病毒感染小鼠中IFN-β的产生(图3)。
实施例7：PA-X1片剂的制备
PA-X1 1000g,药用淀粉100g，混合均匀，用适量乙醇作为粘合剂制粒，干燥，经整粒机整粒，压片，每片0.30g，口服，每次1-2片，每日两次。
实施例8：PA-X1胶囊剂的制备
PA-X1 1000g,药用淀粉100g，混合均匀，用适量乙醇作为粘合剂制粒，干燥，经整粒机整粒，装0#胶囊，每粒0.30g，口服，每次1-2粒，每日两次。
实施例9：PA-X1颗粒剂的制备
PA-X1粒机整粒，分装即得，口服，每次5g，每日两次
实施例10：PA-X1饮料的制备
PA-X1 100g,食用纯净水1000mL，糖粉500g，适当稳定剂和调香剂，混合均匀，，分装即得，口服，每次10mL，每日两次。
实施例11：PA-X2片剂的制备
PA-X2 1000g,药用淀粉100g，混合均匀，用适量乙醇作为粘合剂制粒，干燥，经整粒机整粒，压片，每片0.30g，口服，每次1-2片，每日两次。
实施例12：PA-X2胶囊剂的制备
PA-X2 1000g,药用淀粉100g，混合均匀，用适量乙醇作为粘合剂制粒，干燥，经整粒机整粒，装0#胶囊，每粒0.30g，口服，每次1-2粒，每日两次。
实施例13：PA-X2颗粒剂的制备
PA-X2粒机整粒，分装即得，口服，每次5g，每日两次
实施例14：PA-X2饮料的制备
PA-X2 100g,食用纯净水1000mL，糖粉500g，适当稳定剂和调香剂，混合均匀，分装即得，口服，每次10mL，每日两次。
Claims (8)
1.一种倍半萜类衍生物，其特征在于，它具有以下结构式I、II、III或IV所示结构：
其中，结构式(I)～(IV)中，R1各自独立地选自苯甲酸酯基，对羟基苯甲酸酯基，多羟基苯甲酸酯基，对甲氧基苯甲酸酯基，多甲氧基苯甲酸酯基，氟、氯、溴取代的苯甲酸酯基，氢。
2.根据权利要求1所述的倍半萜类衍生物，其特征在于，优选具有结构式I所示结构，其中，R1优选为苯甲酸酯基或对羟基苯甲酸酯基。
3.一种权利要求1所述倍半萜类衍生物在制备治疗病毒感染疾病的药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述病毒包括新冠病毒、水疱性口炎病毒VSV-G、艾滋病病毒、丙型肝炎病毒、乙型脑炎病毒、流感病毒、脊髓灰质炎病毒、柯萨奇病毒、登革热病毒、轮状病毒、烟草花叶病毒、麻疹病毒、腮腺炎病毒、埃博拉病毒、马尔堡病毒、泡疹病毒和腺病毒。
5.根据权利要求3所述的应用，其特征在于，所述倍半萜类衍生物可与药用载体和/或食用载体组合。
6.根据权利要求5所述的应用，其特征在于，所述倍半萜类衍生物以治疗有效剂量包含于所述药物中。
7.根据权利要求6所述的应用，其特征在于，所述治疗有效剂量能够激活异质性胞核核糖核蛋白A2/B1，上调内源性I型干扰素。
8.根据权利要求5所述的应用，其特征在于，所述药物包括口服制剂和非口服给药制剂；所述口服制剂包括片剂、丸剂、胶囊剂、颗粒剂、微囊片剂、混悬剂、滴丸、口服液体；所述非口服给药制剂包括注射剂、气雾剂、栓剂、皮下给药剂型。
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| PCT/CN2022/086210 WO2023178740A1 (zh) | 2022-03-23 | 2022-04-12 | 一种倍半萜类衍生物及其在制备广谱抗病毒药物中的应用 |
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| ANJU CHOORAKOTTAYIL PUSHKARAN等: "A phytochemical-based medication search for the SARS-CoV-2 infection by molecular docking models towards spike glycoproteins and main proteases", 《RSC ADV.》, vol. 11, pages 12003 - 12014 * |
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