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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 907-919. doi: 10.19723/j.issn.1671-167X.2022.05.018

• 论著 • 上一篇    下一篇

荆防颗粒中抑制新型冠状病毒蛋白酶3CLpro及PLpro的活性成分

尚展鹏,易阳,余蓉,范婧婧,黄昱曦,乔雪,叶敏*()   

  1. 北京大学药学院天然药物及仿生药物国家重点实验室，北京大学云南白药国际医学研究中心，北京 100191
  • 收稿日期:2022-05-15 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 叶敏 E-mail:yemin@bjmu.edu.cn
  • 作者简介:叶敏，北京大学药学院教授，生药学专业博士生导师。1993—2000年在北京中医药大学学习，获得学士及硕士学位。2003年毕业于北京大学，获生药学专业博士学位。2003—2007年在北京大学药学院、耶鲁大学等地从事博士后研究。2007年12月受聘于北京大学药学院，2012年晋升为教授。曾获得国家杰出青年科学基金项目资助和茅以升北京青年科技奖。
    主要研究领域为中药药效物质及质量分析和天然药物生物合成与生物催化。发展了针对中药复杂体系的新分析方法，阐明了甘草等常用中药的药效成分，发现了多个有药用价值的活性分子。从药用植物中发现了一系列碳糖基转移酶等生物合成关键酶，通过晶体结构分析阐明其催化机制，并建立绿色高效的生物催化方法，应用于中药药效成分的酶合成与结构优化。发表SCI论文230余篇，累计被引用7 000余次。目前担任国务院学位委员会第八届药学学科评议组成员、国家药典委员、中国植物学会药用植物及植物药专业委员会副主任委员、世界中医药学会联合会中药分析专业委员会副会长、J Ethnopharmacol和Pharm Biol期刊副主编
  • 基金资助:
    国家自然科学基金(81725023);国家自然科学基金(82122073);国家自然科学基金(82003614)

Bioactive compounds of Jingfang Granules against SARS-CoV-2 virus proteases 3CLpro and PLpro

Zhan-peng SHANG,Yang YI,Rong YU,Jing-jing FAN,Yu-xi HUANG,Xue QIAO,Min YE*()   

  1. State Key Laboratory of Natural and Biomimetic Drugs, Peking University-Yunnan Baiyao International Medical Research Center, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
  • Received:2022-05-15 Online:2022-10-18 Published:2022-10-14
  • Contact: Min YE E-mail:yemin@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(81725023);the National Natural Science Foundation of China(82122073);the National Natural Science Foundation of China(82003614)

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摘要：

目的: 荆防颗粒是新型冠状病毒肺炎预防及轻症治疗的推荐用药，本文结合化学成分分析及活性检测，阐明其潜在的活性成分。方法: 采用酶学方法测定荆防颗粒提取物对新型冠状病毒3-chymotrypsin-like protease (3CLpro)、papain like protease (PLpro)、spike protein receptor-binding domain (S-RBD)及人cyclooxygenase-2 (COX-2)的抑制活性，利用氨水引咳小鼠模型测试其止咳作用；基于liquid chromatography-mass spectrometry(LC/MS)技术对荆防颗粒进行化学成分定性、定量分析，阐明其化学组成；采用酶学实验、分子对接、定点突变等方法测定荆防颗粒中抑制3CLpro、PLpro的主要活性成分并阐明可能的作用机制。结果: 荆防颗粒提取物对新型冠状病毒3CLpro、PLpro蛋白酶具有一定的抑制作用，且具有COX-2抑制活性及止咳药效。进一步在荆防颗粒鉴定了56个成分，其中16个成分经与对照品比对，准确鉴定其化学结构，并测定了其含量，总量为2 498.8 μg/g。16个成分中的主要成分升麻素苷对3CLpro和PLpro均具有显著的抑制活性，8 μmol/L的抑制率分别为76.8%和78.2%；新橙皮苷、柚皮苷对PLpro有抑制活性，8 μmol/L的抑制率分别为53.5%和46.1%。分子对接结果表明，升麻素苷可与3CLpro、PLpro活性口袋的氨基酸残基形成氢键，结合能分别为-7.7和-7.3 kcal/mol。定点突变结果表明，氨基酸残基K157是升麻素苷与PLpro相互作用的重要活性位点。结论: 荆防颗粒的主要成分升麻素苷、新橙皮苷、柚皮苷等具有抑制新型冠状病毒3CLpro及PLpro的活性，为荆防颗粒的临床合理使用提供了依据。

关键词: 荆防颗粒, 活性成分, 新型冠状病毒, 3CLpro, PLpro

Abstract:

Objective: Jingfang Granules have been recommended for the prevention and treatment of corona virus disease 2019 (COVID-19). Through chemical analysis and bioactivity evaluation, this study aims to elucidate the potential effective components of Jingfang Granules. Methods: The inhibitory acti-vities of Jingfang Granules extract against 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro), spike protein receptor-binding domain (S-RBD) and human cyclooxygenase-2 (COX-2) were evaluated using enzyme assay. The antitussive effects were evaluated using the classical ammonia-induced cough model. The chemical constituents of Jingfang Granules were qualitatively and quantitatively analyzed by liquid chromatography-mass spectrometry (LC/MS). The 3CLpro and PLpro inhibitory activities of the major compounds were determined by enzyme assay, molecular docking, and site-directed mutagenesis. Results: Jingfang Granules exhibited 3CLpro and PLpro inhibitory activities, as well as COX-2 inhibitory and antitussive activities. By investigating the MS/MS behaviors of reference standards, a total of fifty-six compounds were characterized in Jingfang Granules. Sixteen of them were unambiguously identified by comparing with reference standards. The contents of the 16 major compounds were also determined, and their total contents were 2 498.8 μg/g. Naringin, nodakenin and neohesperidin were three dominating compounds in Jingfang Granules, and their contents were 688.8, 596.4 and 578.7 μg/g, respectively. In addition, neohesperidin and naringin exhibited PLpro inhibitory activities, and the inhibition rates at 8 μmol/L were 53.5% and 46.1%, respectively. Prim-O-glucosylcimifugin showed significant inhibitory activities against 3CLpro and PLpro, and the inhibitory rates at 8 μmol/L were 76.8% and 78.2%, respectively. Molecular docking indicated that hydrogen bonds could be formed between prim-O-glucosylcimifugin and amino acid residues H163, E166, Q192, T190 of 3CLpro (binding energy, -7.7 kcal/mol) and K157, D164, R166, E167, T301 of PLpro(-7.3 kcal/mol), respectively. Site-directed mutagenesis indicated amino acid residue K157 was a key active site for the interaction between prim-O-glucosylcimifugin and PLpro. Conclusion: Prim-O-glucosylcimifugin, neohesperidin, and naringin as the major compounds from Jingfang Granules could inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus proteases 3CLpro and PLpro. The results are valuable for rational clinical use of Jingfang Granules.

Key words: Jingfang Granules, Effective components, Severe acute respiratory syndrome coronavirus 2, 3-chymotrypsin-like protease, Papain like protease

中图分类号: 

  • R932

图1

化学对照品的结构式"

图2

荆防颗粒提取物的3CLpro、PLpro、S-RBD、COX-2抑制活性及止咳活性"

表1

LC/MS方法鉴定荆防颗粒的化学成分"

No. tR/min Precursor ion Formula Ion mode MS/MS Identification Type Source Reference
P1 1.51 353.087 4 C16H18O9 - 191.055 8, 179.034 7 Cryptochlorogenic acid Phenolic acid JingJie [22]
P2 1.78 353.087 4 C16H18O9 - 191.055 7 Neochlorogenic acid Phenolic acid JingJie [22]
P3 2.02 563.140 2 C26H28O14 - 383.076 7, 353.066 3 Schaftoside Flavonoid GanCao [23]
P4 2.10 515.118 7 C25H24O12 - 191.055 8, 179.034 7 Isochlorogenic acid A Phenolic acid JingJie [22]
P5 2.47 179.034 7 C9H8O4 - 135.044 9 Caffeic acid Phenolic acid JingJie [22]
P6 2.49 469.169 8 C22H28O11 + 307.117 0, 261.111 8 Prim-O-glucosylcimifugin isomer Chromone ShengMa [24]
P7(1) 2.58 469.169 6 C22H28O11 + 307.117 0, 261.111 9 Prim-O-glucosylcimifugin Chromone ShengMa [24]
P8 2.74 577.155 8 C27H30O14 - 383.076 9, 353.066 2 Violanthin Flavonoid GanCao [23]
P9(2) 3.43 549.160 8 C26H30O13 - 255.065 9, 135.008 5 Liquiritin apioside Flavonoid GanCao [23]
P10 3.55 595.166 1 C27H32O15 - 459.113 9, 287.055 6, 151.003 4 Neoeriocitrin Flavonoid GanCao [25]
P11(3) 3.81 417.118 6 C21H22O9 - 255.065 9, 135.008 5, 119.049 9 Liquiritin Flavonoid GanCao [23]
P12 3.93 447.092 5 C21H20O11 - 285.040 0 Luteolin-7-glucoside Flavonoid JingJie [25]
P13 4.44 515.118 9 C25H24O12 - 191.055 8, 179.034 7, 173.045 2 Isochlorogenic acid B Phenolic acid JingJie [22]
P14(4) 4.74 579.169 8 C27H32O14 - 271.060 9, 151.003 4 Narirutin Flavonoid ZhiKe [25]
P15(5) 4.78 307.115 6 C16H18O6 + 289.106 5, 289.106 5, 235.059 7 Cimifugin Chromone ShengMa [24]
P16 4.78 409.147 1 C20H24O9 + 187.038 7, 159.043 7 Nodakenin Coumarin FangFeng [26]
P17 4.78 229.084 6 C14H12O3 + 187.038 7, 159.043 7 Angenomalin Coumarin QiangHuo [27]
P18(6) 4.79 407.133 2 C20H23O9 - 227.070 9 Nodakenin Coumarin QianHu [26]
P19 4.82 577.155 5 C27H30O14 - 269.045 2 Rhoifolin/isomer Flavonoid ZhiKe [25]
P20(7) 5.17 579.169 6 C27H32O14 - 459.114 9, 271.060 8, 151.003 4 Naringin Flavonoid ZhiKe [25]
P21(8) 5.29 451.159 5 C22H28O10 - 271.097 2 5-O-methylvisammioside Chromone FangFeng [24]
P22 5.30 453.173 3 C22H28O10 + 291.122 0, 273.111 5, 231.064 7 4′-O-β-D-glucosyl-5-O-methylvisamminol Chromone FangFeng [24]
P23 5.46 515.118 7 C25H24O12 - 191.055 8, 179.034 7, 173.045 1 Isochlorogenic acid C Phenolic acid JingJie [22]
P24(9) 5.55 609.180 3 C28H34O15 - 301.071 2, 151.003 3 Hesperidin Flavonoid ZhiKe [25]
P25(10) 5.72 359.076 9 C18H16O8 - 179.034 7, 161.024 1 Rosmarinic acid Phenolic acid JingJie [22]
P26(11) 5.87 609.180 1 C28H34O15 - 301.071 3, 151.003 2 Neohesperidin Flavonoid ZhiKe [25]
P27 6.11 549.160 9 C26H30O13 - 255.065 9, 135.008 5 Isoliquiritin apioside Flavonoid GanCao [23]
P28 6.20 463.124 1 C22H24O11 - 301.071 2 Hyperin Flavonoid JingJie [25]
P29 6.54 417.118 7 C21H22O9 - 255.065 9, 135.008 6, 119.049 9 Isoliquiritin Flavonoid GanCao [23]
P30 7.47 255.065 9 C15H12O4 - 135.008 5, 119.049 9 Liquiritigenin Flavonoid GanCao [23]
P31 7.65 1237.548 4 C57H90O29 - 695.364 2, 519.332 2 Platycodin J Saponin JieGeng [28]
P32 7.71 1091.526 6 C52H84O24 - 681.384 7, 457.331 8 Deapioplatycodin D Saponin JieGeng [28]
P33 7.76 291.121 0 C16H18O5 + 273.111 4, 243.064 5, 219.064 8 5-O-methylvisamminol Coumarin FangFeng [24]
P34 7.77 285.040 0 C15H10O6 - 151.003 3, 133.029 0 Luteolin Flavonoid JingJie [25]
P35 7.80 1369.624 8 C63H102O32 - 827.443 2, 503.337 3, 469.155 4 Polygalacin D2 Saponin JieGeng [28]
P36(12) 7.83 1223.568 2 C57H92O28 - 681.384 7, 469.155 4 Platycodin D Saponin JieGeng [28]
P37 7.89 1105.506 3 C52H82O25 - 895.426 8, 485.290 1 Platyconic acid C Saponin JieGeng [28]
P38 8.39 1265.579 4 C59H94O29 - 681.384 7, 469.155 7 Platycodin A Saponin JieGeng [28]
P39 8.45 895.396 4 C44H64O19 - 351.056 4, 193.035 1 Uralsaponin F Saponin GanCao [23]
P40 8.66 983.449 7 C48H72O21 - 821.396 2, 351.056 6 Licorice-saponin A3 Saponin GanCao [23]
P41 9.03 271.060 9 C15H12O5 - 151.003 4, 119.050 0 Naringenin Flavonoid ZhiKe [25]
P42 9.18 879.402 5 C44H64O18 - 351.056 2, 193.034 9 22β-acetoxyl-glycyrrhizin Saponin GanCao [23]
P43 9.36 837.390 9 C42H62O17 - 351.056 4, 193.035 0 Licorice-saponin G2 Saponin GanCao [23]
P44 9.63 301.071 5 C16H14O6 - 286.048 0, 164.011 3, 151.003 4 Hesperetin Flavonoid JingJie [25]
P45 9.92 377.160 0 C20H24O7 + 277.106 6, 205.049 3 Angelol A Coumarin DuHuo [27]
P46 10.24 837.390 4 C42H62O17 - 351.056 6, 193.035 0 Uralsaponin N Saponin GanCao [23]
P47 10.29 255.065 9 C15H12O4 - 135.008 6, 119.050 0 Isoliquiritigenin Flavonoid GanCao [23]
P48 10.36 377.157 6 C20H24O7 + 277.106 4, 205.049 1 Angelol B Coumarin DuHuo [27]
P49(13) 10.88 821.393 3 C42H62O16 - 351.056 4, 193.034 9 Glycyrrhizic acid Saponin GanCao [23]
P50(14) 11.89 779.457 2 C42H68O13 - 617.404 7, 423.328 9 Saikosaponin A Saponin ChaiHu [29]
P51 12.11 823.411 4 C42H64O16 - 351.056 4, 193.034 9 Licorice-saponin J2 Saponin GanCao [23]
P52 12.29 779.457 4 C42H68O13 - 617.404 9, 471.347 1 Saikosaponin B2 Saponin ChaiHu [29]
P53 12.38 779.457 5 C42H68O13 - 617.404 8, 455.315 9 Saikosaponin A /isomer Saponin ChaiHu [29]
P54 12.53 807.416 8 C42H64O15 - 351.056 3, 193.034 9 Licorice-saponin B2 Saponin GanCao [23]
P55(15) 14.10 245.116 3 C15H16O3 + 189.054 3, 131.049 0 Osthole Coumarin QiangHuo [27]
P56(16) 14.55 327.121 0 C19H18O5 + 227.069 7, 83.049 6 Praeruptorin A Coumarin QianHu [26]

图3

荆防颗粒的LC/UV及LC/MS谱图"

图4

荆防颗粒中代表性成分的MS/MS质谱图"

图5

荆防颗粒16个主要成分的LC/PRM-MS定量分析谱图"

表2

荆防颗粒中16个化合物的定量分析方法相关参数"

No. Compound Ion mode Collision energy/% Precursor ion Product ion Calibration equation r2 Range/(μg /L)
IS Puerarin - 35 415.103 7 295.061 0
1 Prim-O-glucosylcimifugin + 40 469.171 1 307.117 7 y=0.000 687+0.005 71x-2.370 37e-7x2 0.998 1 19.5-5 000.0
2 Liquiritin apioside - 35 549.161 9 255.066 6 y=0.021 41+0.002 33x-3.857 63e-9x2 0.993 8 78.1-5 000.0
3 Liquiritin - 20 417.119 6 255.066 6 y=0.039 28+0.004 03x-4.373 89e-8x2 0.995 1 78.1-5 000.0
4 Narirutin - 20 579.172 9 271.061 2 y=0.003 57+0.002 08x 0.997 0 19.5-5 000.0
5 Cimifugin + 60 307.117 9 235.060 2 y=0.010 25+0.010 77x -2.186 92e-6x2 0.998 9 19.5-1 250.0
6 Nodakenin - 20 453.141 1 227.071 6 y=0.001 55+0.000 38x-6.293 65e-9x2 0.999 4 39.0-10 000.0
7 Naringin - 35 579.172 9 271.061 2 y=0.014 32+0.001 39x-2.927 19e-8x2 0.997 7 39.0-10 000.0
8 5-O-methylvisammioside - 20 451.159 5 271.098 0 y=0.000 24+0.000 11x -5.315 51e-9x2 0.997 2 39.0-2 500.0
9 Hesperidin - 20 609.183 2 301.072 0 y=0.002 58+0.002 51x-1.413 47e-7x2 0.999 0 19.5-2 500.0
10 Rosmarinic acid - 20 359.077 4 161.024 5 y=0.001 05+0.001 80x +3.992 36e-9x2 0.999 1 19.5-5 000.0
11 Neohesperidin - 35 609.183 2 301.072 0 y=0.028 16+0.002 63x-9.288 72e-8x2 0.998 9 78.1-10 000.0
12 Platycodin D - 30 1 223.570 9 681.386 2 y=-0.000 21+0.001 140x 0.980 1 19.5-5 000.0
13 Glycyrrhizic acid - 50 821.397 7 351.057 5 y=0.245 84+0.001 14x-2.767 58e-8x2 0.999 1 19.5-2 500.0
14 Saikosaponin A - 35 779.458 4 617.406 3 y=-0.000 35+0.000 48x -8.079 04e-8x2 0.998 5 9.8-1 250.0
15 Osthole + 30 245.117 5 189.054 7 y=0.039 98+0.015 82x-9.182 13e-7x2 0.994 9 19.5-5 000.0
16 Praeruptorin A - 20 327.122 7 203.034 0 y=1.993 35+0.029 20x+4.227 01e-6x2 0.990 4 19.5-1 250.0

表3

16个化合物定量分析的方法学考察"

No. Repeatability /% Stability/% Precision Recovery
Intraday/% Interday/% Detection/ng Spiked/ng Recovery/% RSD/%
1 4.5 11.2 9.7 10.7 213.0 200.0 106.6 7.9
2 9.2 7.1 4.1 1.8 52.0 50.0 104.1 4.5
3 6.5 4.0 2.9 2.6 56.0 50.0 113.0 4.5
4 8.4 7.8 5.3 3.0 230.0 200.0 115.1 3.6
5 5.4 6.8 2.9 13.6 60.0 50.0 120.2 9.4
6 5.9 4.7 3.6 2.8 880.0 1 000.0 88.0 3.1
7 7.6 7.5 5.7 2.4 879.0 1 000.0 87.9 4.3
8 9.7 3.5 6.7 0.7 62.0 50.0 123.0 4.3
9 7.9 4.9 6.2 1.7 204.0 200.0 101.8 7.0
10 4.1 3.8 2.7 4.9 56.0 50.0 111.1 3.0
11 8.3 4.0 3.8 2.2 1 024.0 1 000.0 102.4 4.8
12 13.2 15.6 15.2 3.0 47.0 50.0 93.8 13.7
13 14.4 9.0 4.6 8.3 229.0 200.0 114.5 4.2
14 4.8 8.9 3.8 5.1 116.0 100.0 114.5 5.2
15 5.1 10.2 6.0 10.6 60.0 50.0 119.7 8.2
16 7.3 12.4 6.5 15.5 101.0 100.0 101.1 7.1

图6

荆防颗粒中16个主要成分的含量及其3CLpro和PLpro抑制活性"

图7

升麻素苷与3CLpro和升麻素苷、新橙皮苷、柚皮苷与PLpro的分子对接结果以及对PLproK157A突变体的抑制活性"

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