甘草抗病毒作用机制与转化应用研究进展

doi:10.13560/j.cnki.biotech.bull.1985.2026-0304

摘要/Abstract

摘要：

甘草（Glycyrrhiza spp.）作为传统中药，其抗病毒作用源于多组分、多靶点的协同效应。主要活性成分三萜皂苷（如甘草甜素）、黄酮及多糖，通过直接干预病毒生命周期和调节宿主免疫双重机制发挥作用。直接抗病毒机制包括竞争性抑制病毒吸附（如阻断SARS-CoV-2与ACE2结合）、抑制关键酶活性（如流感病毒RdRp）等；免疫调节机制则体现为激活树突状细胞、促进干扰素分泌等天然免疫，同时通过调控NF-κB等通路抑制过度炎症反应。研究表明，甘草对SARS-CoV-2、流感病毒、肝炎病毒、伪狂犬病毒等多种病毒均显示抑制活性。目前，甘草甜素注射液已用于慢性乙型肝炎的临床治疗，在畜牧养殖中作为饲料添加剂或疫苗佐剂也展现出潜力。然而，其临床应用仍面临口服生物利用度低、化学成分复杂致质控困难、质量控制标准不统一、种属差异及长期安全性等挑战。未来研究需通过结构修饰、新型递药系统改善药学特性，并结合高质量临床与田间试验，建立化学-生物学结合的质量标准，以推动其成为应对新发传染病和保障动物健康的现代化制剂。

关键词: 甘草, 甘草活性成分, 抗病毒, 免疫调节

Abstract:

Glycyrrhiza as a traditional Chinese medicine exerts its antiviral effects through the synergistic interactions of multiple components targeting multiple pathways.Its main active constituents, including triterpenoid saponins (e.g., glycyrrhizin), flavonoids, and polysaccharides, function via a dual mechanism involving direct intervention in the viral life cycle and modulation of host immunity. Direct antiviral actions encompass competitively inhibiting viral adsorption (e.g., blocking SARS-CoV-2 binding to ACE2) and suppressing the activity of key viral enzymes (e.g., influenza virus RdRp). Immunomodulatory mechanisms involve activating innate immune responses, such as stimulating dendritic cells and promoting interferon secretion, while simultaneously regulating pathways like NF-κB to suppress excessive inflammation. Studies have shown that licorice exhibits inhibitory activity against a broad spectrum of viruses, including SARS-CoV-2, influenza virus, hepatitis viruses, and pseudorabies virus. Currently, glycyrrhizin injection is clinically used for treating chronic hepatitis B, and its potential as a feed additive or vaccine adjuvant in animal husbandry has been demonstrated. However, its clinical application still faces challenges such as low oral bioavailability, difficulties in quality control due to complex chemical composition, species differences, and long-term safety concerns. Future research should focus on improving its pharmaceutical properties through structural modification and novel drug delivery systems, combined with high-quality clinical and field trials, and establishing integrated chemical-biological quality standards. This will advance its development into modernized preparations for addressing emerging infectious diseases and ensuring animal health.

Key words: glycyrrhiza, bioactive components of glycyrrhiza, antiviral, immunomodulation

朱婉茹, 孟令品, 高峥, 宋扬, 温树波. 甘草抗病毒作用机制与转化应用研究进展[J]. 生物技术通报, doi: 10.13560/j.cnki.biotech.bull.1985.2026-0304.

ZHU Wan-ru, MENG Ling-pin, GAO Zheng, SONG Yang, WEN Shu-bo. Research Advances in the Antiviral Mechanism and Translational Applications of Glycyrrhiza[J]. Biotechnology Bulletin, doi: 10.13560/j.cnki.biotech.bull.1985.2026-0304.

图/表 6

参考文献 88

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类别 Category	抗病毒活性组分 Antiviral components	文献 Reference
三萜皂苷类	甘草甜素	［7， 15， 27-41］
	甘草甜素衍生物
	甘草酸
	甘草次酸
	甘草次酸的衍生物
	甘草皂苷
黄酮类	甘草黄酮	［20， 29， 42-48］
	甘草苷
	芹糖甘草苷
	甘草素
	异甘草素
	甘草查尔酮A
	光甘草定
	甘草糖苷E
多糖类	甘草多糖	［5， 49-51］
酚类	甘草酚	［52］
	异甘草酚
	甘草香豆素
其他	甘草醛Q	［53］
生物碱类	5，6，7，8-四氢-2，4-二甲基喹啉	［54］
生物碱类	5，6，7，8-四氢-4-甲基喹啉	［54］
挥发油类	甘草挥发油（例：十九烷）	［55］

类别 Category	抗病毒活性组分 Antiviral components	文献 Reference
三萜皂苷类	甘草甜素	［7， 15， 27-41］
	甘草甜素衍生物
	甘草酸
	甘草次酸
	甘草次酸的衍生物
	甘草皂苷
黄酮类	甘草黄酮	［20， 29， 42-48］
	甘草苷
	芹糖甘草苷
	甘草素
	异甘草素
	甘草查尔酮A
	光甘草定
	甘草糖苷E
多糖类	甘草多糖	［5， 49-51］
酚类	甘草酚	［52］
	异甘草酚
	甘草香豆素
其他	甘草醛Q	［53］
生物碱类	5，6，7，8-四氢-2，4-二甲基喹啉	［54］
生物碱类	5，6，7，8-四氢-4-甲基喹啉	［54］
挥发油类	甘草挥发油（例：十九烷）	［55］

病毒Virus	甘草活性成分Active component	主要作用机制Primary mechanism	实验模型Experimental model	效果Efficacy	参考文献Reference
SARS-CoV-2	甘草根水提物、甘草酸	抑制病毒主蛋白酶（Mpro）	体外（Vero E6细胞）	水溶液甘草根提取物在2 mg/mL亚毒浓度下显示抗病毒效果；甘草酸在2 000 μmol/L（1.6 mg/mL）完全抑制Mpro活性，在30 μmol/L（0.024 mg/mL）时其活性降低70.3%	［33］
PRRSV	Glycyrrhizin	抑制病毒的内化过程	体外（MARC-145细胞）	800 μmol/L甘草酸可抑制PRRSV与MARC-145细胞的结合，在0.001与0.000 1 PFU/细胞MOI下感染率分别降低15%和30%，并在穿透阶段抑制其内化，使病毒滴度降低约1 000倍	［29］
PRV	Glycyrrhiza polysaccharide （GCP）	抑制PRV附着与内化	体外（PK-15， Vero细胞）	GCP通过靶向病毒感染早期阶段发挥抑制作用，效果呈剂量依赖性。其中，共处理效果最强（抑制gB蛋白80.6%，病毒滴度42.6%），预处理无效，后处理效果较弱（17.7%-25.9%），且600 μg/mL为最适浓度	［50］
HRSV	Radix glycyrrhizae and （18β-GA）	可能抑制病毒在宿主细胞上的附着和侵入	体外（HEp-2， A549细胞）	甘草根在病毒接种前给药更有效，能抑制病毒附着和穿透；300 μg/mL甘草根显著减少细胞内和悬浮液中的病毒量；甘草根刺激黏膜细胞分泌IFN-β抵抗病毒感染	［60］
RSV	Glycyrrhizin	减少病毒复制	体外（人支气管上皮细胞）	Glycyrrhizin剂量依赖性地抑制了感染RSV的永生化和原发人类支气管上皮细胞中的HMGB1上调	［68］
NDV	甘草水提取物	抑制病毒的复制	鸡胚	60 mg/100 mL的甘草提取物在胚胎卵中未产生任何毒性，并显示出抗病毒活性	［69］
HIV/HIV-1/NSI-HIV	Glycyrrhizin相关化合物	降低膜流动性、抑制蛋白激酶C（PKC）、免疫调节	体外（多种免疫细胞系）	0.6 mmol/L完全抑制HIV诱导噬斑形成；0.3和0.6 mmol/L完全抑制MT-4细胞HIV病变效应和抗原表达；Glycyrrhizin在0.075-0.6 mmol/L剂量依赖降低MOLT-4细胞的蛋白激酶C（PKC）活性，1.2 mmol/L浓度部分抑制HIV-1颗粒与MT-4细胞的吸附和巨细胞形成；Glycyrrhizin通过诱导β趋化因子抑制外周血单个核细胞（PBMC）培养物中非合胞体诱导型HIV变异株（NSI-HIV）复制	［36， 56， 70-71］
IAV	Glycyrrhizin	降低病毒摄取；干扰病毒基因复制与蛋白合成	体外（人肺细胞；噬菌体）	Glycyrrhizin通过作用于细胞膜降低病毒内吞活性；HMGB1结合DNA来抑制IAV聚合酶活性	［6， 37， 64］
HSV-1	Glycyrrhizin	直接作用于病毒颗粒；潜在结合阻断	体外（人类非整倍HEp2细胞）	对HSV-1聚合酶表现出高结合能评分（-22.45 kcal/mol）	［63］
VZV	Glycyrrhizin	抑制病毒颗粒的穿透、脱壳或释放	体外（人胚胎成纤维细胞）	2.4 mmol/L浓度在37 ℃下处理30 min，可灭活99%以上的病毒颗粒	［31］
EBV	甘草酸衍生物	抑制病毒的吸附和穿透	体外（Raji细胞）	在20-90 μmol/L浓度范围内，可剂量依赖性地降低病毒基因拷贝数，半数有效浓度（EC₅₀）为25 μmol/L	［34］

病毒Virus	甘草活性成分Active component	主要作用机制Primary mechanism	实验模型Experimental model	效果Efficacy	参考文献Reference
SARS-CoV-2	甘草根水提物、甘草酸	抑制病毒主蛋白酶（Mpro）	体外（Vero E6细胞）	水溶液甘草根提取物在2 mg/mL亚毒浓度下显示抗病毒效果；甘草酸在2 000 μmol/L（1.6 mg/mL）完全抑制Mpro活性，在30 μmol/L（0.024 mg/mL）时其活性降低70.3%	［33］
PRRSV	Glycyrrhizin	抑制病毒的内化过程	体外（MARC-145细胞）	800 μmol/L甘草酸可抑制PRRSV与MARC-145细胞的结合，在0.001与0.000 1 PFU/细胞MOI下感染率分别降低15%和30%，并在穿透阶段抑制其内化，使病毒滴度降低约1 000倍	［29］
PRV	Glycyrrhiza polysaccharide （GCP）	抑制PRV附着与内化	体外（PK-15， Vero细胞）	GCP通过靶向病毒感染早期阶段发挥抑制作用，效果呈剂量依赖性。其中，共处理效果最强（抑制gB蛋白80.6%，病毒滴度42.6%），预处理无效，后处理效果较弱（17.7%-25.9%），且600 μg/mL为最适浓度	［50］
HRSV	Radix glycyrrhizae and （18β-GA）	可能抑制病毒在宿主细胞上的附着和侵入	体外（HEp-2， A549细胞）	甘草根在病毒接种前给药更有效，能抑制病毒附着和穿透；300 μg/mL甘草根显著减少细胞内和悬浮液中的病毒量；甘草根刺激黏膜细胞分泌IFN-β抵抗病毒感染	［60］
RSV	Glycyrrhizin	减少病毒复制	体外（人支气管上皮细胞）	Glycyrrhizin剂量依赖性地抑制了感染RSV的永生化和原发人类支气管上皮细胞中的HMGB1上调	［68］
NDV	甘草水提取物	抑制病毒的复制	鸡胚	60 mg/100 mL的甘草提取物在胚胎卵中未产生任何毒性，并显示出抗病毒活性	［69］
HIV/HIV-1/NSI-HIV	Glycyrrhizin相关化合物	降低膜流动性、抑制蛋白激酶C（PKC）、免疫调节	体外（多种免疫细胞系）	0.6 mmol/L完全抑制HIV诱导噬斑形成；0.3和0.6 mmol/L完全抑制MT-4细胞HIV病变效应和抗原表达；Glycyrrhizin在0.075-0.6 mmol/L剂量依赖降低MOLT-4细胞的蛋白激酶C（PKC）活性，1.2 mmol/L浓度部分抑制HIV-1颗粒与MT-4细胞的吸附和巨细胞形成；Glycyrrhizin通过诱导β趋化因子抑制外周血单个核细胞（PBMC）培养物中非合胞体诱导型HIV变异株（NSI-HIV）复制	［36， 56， 70-71］
IAV	Glycyrrhizin	降低病毒摄取；干扰病毒基因复制与蛋白合成	体外（人肺细胞；噬菌体）	Glycyrrhizin通过作用于细胞膜降低病毒内吞活性；HMGB1结合DNA来抑制IAV聚合酶活性	［6， 37， 64］
HSV-1	Glycyrrhizin	直接作用于病毒颗粒；潜在结合阻断	体外（人类非整倍HEp2细胞）	对HSV-1聚合酶表现出高结合能评分（-22.45 kcal/mol）	［63］
VZV	Glycyrrhizin	抑制病毒颗粒的穿透、脱壳或释放	体外（人胚胎成纤维细胞）	2.4 mmol/L浓度在37 ℃下处理30 min，可灭活99%以上的病毒颗粒	［31］
EBV	甘草酸衍生物	抑制病毒的吸附和穿透	体外（Raji细胞）	在20-90 μmol/L浓度范围内，可剂量依赖性地降低病毒基因拷贝数，半数有效浓度（EC₅₀）为25 μmol/L	［34］

适应症/病毒Indication/Virus	研究类型 Study type	干预措施 Intervention	主要发现/结局指标 Key findings/Outcome measures	证据强度/局限性 Strength of evidence/Limitations	参考文献 Reference
日本慢性乙肝	动物实验：豚鼠	甘草素静脉注射	抑制HBsAg分泌；给药后1 h和4 h肝中甘草酸苷浓度分别为4.2和1.3 μg/g	改善肝功能，偶可实现肝炎完全康复	［38］
高致病性甲型流感H5N1	肺上皮细胞（A549）	注射用甘草酸制剂（SNMC）	具剂量依赖性双效作用：低浓度抗炎（抑制CXCL10， IL-6， CCL2， CCL5）；高浓度直接抗病毒。抑制病毒诱导ROS，下游阻断NF-κB/JNK/p38通路激活	可能是治疗H5N1的潜在补充药物	［39］
上呼吸道感染	病例对照	静脉滴注甘草酸（0.2%， 40 mL）	平均住院时间更短，24-48 h内平均最高体温更低，治疗费用更低，无不良事件报告	对无急性细菌感染的URTI患者可能具有临床获益	［40］
鼻病毒	上市药物	hochu-ekki-to（日本）	降低ICAM-1，阻断病毒RNA进入细胞质，抑制RV14感染	治疗普通感冒，降低COPD患者感冒发作频率	［84］
肺炎	人肺成纤维细胞（HFL-1）	GL/GA/11-脱氧-GL/异构-GL/异构-30-OH-GL/同型-30-OH-GL	异构-30-OH-GL和同型-30-OH-GL抑制IL-8效果显著增强（IC50约52-60 μg/mL），细胞毒性大幅降低（CC30>100 μg/mL）	成为具开发潜力的候选化合物	［85］
丙型肝炎	小鼠模型	甘草酸制剂SNMC	剂量依赖性抑制肝脂肪变性；不影响肝脏铁含量，减轻肝线粒体超微结构改变；激活线粒体β-氧化，增加肉碱棕榈酰转移酶I表达，降低铁过载转基因小鼠肝脏中活性氧的生成	可能通过保护线粒体免受HCV蛋白和铁过载诱导的氧化应激预防肝脂肪变性	［86］
人类免疫缺陷病毒	临床试验	SNMC（100-200 mL或400-800 mL）	CD4计数及CD4/CD8比值部分改善；淋巴细胞母细胞化反应增加，尤以高剂量组显著；肝功能障碍完全改善	高剂量SNMC对HIV感染血友病患者有治疗效果，与AZT联用或更佳	［87］
2019冠状病毒病	临床试验	NRICM101	患者连续给药后在中位数9 d内连续3次检测为阴性，且无不良反应	NRICM101通过抗病毒和抗炎特性干扰疾病进展，有望成为多靶点新冠肺炎防治药物	［88］