药学学报, 2019, 54(5): 838-845
引用本文:
唐克, 张晓雨, 陈勍, 郭颖. 沙粒病毒进入宿主细胞阻断剂3,5,6,7,4'-五甲氧基黄酮的发现及机制研究[J]. 药学学报, 2019, 54(5): 838-845.
TANG Ke, ZHANG Xiao-yu, CHEN Qing, GUO Ying. Effects and mechanism of 3,5,6,7,4'-pentamethoxyflavone for blocking arenavirus entry[J]. Acta Pharmaceutica Sinica, 2019, 54(5): 838-845.

沙粒病毒进入宿主细胞阻断剂3,5,6,7,4'-五甲氧基黄酮的发现及机制研究
唐克, 张晓雨, 陈勍, 郭颖
中国医学科学院、北京协和医学院药物研究所, 新药作用机制研究与药效评价北京市重点实验室, 北京 100050
摘要:
沙粒病毒是有包膜的RNA病毒,现已知其家族中的8种病毒可致人出血热。除胡宁病毒疫苗外,目前尚无针对其他沙粒病毒的疫苗或特效药物批准上市。本研究是在首次发现黄酮类化合物桔皮素的抗沙粒病毒活性的基础上,从34个桔皮素类似物中发现并确认了3,5,6,7,4'-五甲氧基黄酮的抗拉沙病毒的活性(EC50:5.2 μmol·L-1),并初步探讨了其构效关系。研究结果表明,3,5,6,7,4'-五甲氧基黄酮对拉沙病毒的抑制活性是通过阻断病毒融合过程实现的,该化合物对除拉沙病毒外的另外7种致出血热沙粒病毒进入宿主细胞过程也有阻断活性(EC50:0.84~10.2μmol·L-1),其抗毒谱与现有沙粒病毒进入抑制剂相比有明显优势。本研究结果为应对致出血热沙粒病毒的药物研发提供了物质储备,也为寻找和发现广谱抗沙粒病毒活性物质提供线索。
关键词:    沙粒病毒      病毒性出血热      3,5,6,7,4'-五甲氧基黄酮      进入抑制剂     
Effects and mechanism of 3,5,6,7,4'-pentamethoxyflavone for blocking arenavirus entry
TANG Ke, ZHANG Xiao-yu, CHEN Qing, GUO Ying
Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Arenaviruses are enveloped RNA viruses, and eight members in this family are known to cause human hemorrhagic fever. Treatments for the viral hemorrhagic fever (VHF) by arenaviruses are very limited. We have identified the first flavone, tangeretin, with broad-spectrum inhibitory activities on VHF-arenaviruses infection by blocking viral entry. In this study, we evaluated thirty-four tangeretin analogues and found 3,5,6,7,4'-pentamethoxyflavone as a Lassa virus entry inhibitor, with EC50 of 5.2 μmol·L-1, by blocking the viral fusion pro cess. The compound 3,5,6,7,4'-pentamethoxyflavone is effective on all known VHF-arenaviruses, with EC50 range of 0.84-10.2 μmol·L-1. These results suggest that 3,5,6,7,4'-pentamethoxyflavone is able to serve as a start point for discovery of arenavirus entry inhibitors from flavone natural products.
Key words:    arenavirus    viral hemorrhagic fever    3,5,6,7,4'-pentamethoxyflavone    entry inhibitor   
收稿日期: 2018-12-27
DOI: 10.16438/j.0513-4870.2018-1152
基金项目: 国家"重大新药创制"专项(2015ZX09102-023,2018ZX09711001-003-002);中国医学科学院医学与健康科技创新工程(2016-I2M-1-014);国家自然科学基金资助项目(81473256,81273561);北京市科委全市成果转化统筹基金(Z151100000115008);新药作用机制研究与药效评价北京市重点实验室资助项目(BZ0150).
通讯作者: 郭颖,Tel:86-10-63161716,E-mail:yingguo6@imm.ac.cn
Email: yingguo6@imm.ac.cn
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参考文献:
[1] Sarute N, Ross SR. New world arenavirus biology[J]. Annu Rev Virol, 2017, 4:141-158.
[2] Dept, Health U.S. Biosafety in Microbiological and Biomedical Laboratories[M]. 5th ed. Centers for Disease Control and Preven tion, National Institutes of Health, USA, 2010:246-265.
[3] Enserink M. Emerging diseases. New arenavirus blamed for recent deaths in California[J]. Science, 2000, 289:842-843.
[4] Gunther S, Lenz O. Lassa virus[J]. Crit Rev Clin Lab Sci, 2004, 41:339-390.
[5] Yun NE, Walker DH. Pathogenesis of Lassa fever[J]. Viruses, 2012, 4:2031-2048.
[6] Coyle AL. Lassa fever[J]. Nursing, 2016, 46:69-70.
[7] Houlihan C, Behrens R. Lassa fever[J]. BMJ, 2017, 358:j2986.
[8] Nigeria Centre for Disease Control. An Update of Lassa Fever Outbreak in Nigeria[EB/OL]. Disease Situation Reports[2018-12-09]. http://www.ncdc.gov.ng/diseases/sitreps/.
[9] Roberts L. Nigeria hit by unprecedented Lassa fever outbreak[J]. Science, 2018, 359:1201-1202.
[10] Crotty S, Cameron C, Andino R. Ribavirin's antiviral mechanism of action:lethal mutagenesis?[J] J Mol Med, 2002, 80:86-95.
[11] Tang K, He S, Zhang X, et al. Tangeretin, an extract from Citrus peels, blocks cellular entry of arenaviruses that cause viral hemorrhagic fever[J]. Antiviral Res, 2018, 160:87-93.
[12] Zhang X, Tang K, Guo J, et al. Establishment of evaluation system for a cell-based arenavirus entry inhibitor[J]. Acta Pharm Sin (药学学报), 2018, 53:735-742.
[13] Chen Q, Tang K, Zhang X, et al. Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evalua tion of filovirus entry inhibitors[J]. Acta Pharm Sin B, 2018, 8:200-208.
[14] Gong J, Zhang Y, Wu X. Advances in studies on antiviral activi ties of flavoids[J]. Chin Tradit Herb Drugs (中草药), 2008, 39:623-627.
[15] Kumar S, Pandey AK. Chemistry and biological activities of flavonoids:an overview[J]. ScientificWorldJournal, 2013, 2013:162750.
[16] Burri DJ, da Palma JR, Kunz S, et al. Envelope glycoprotein of arenaviruses[J]. Viruses, 2012, 4:2162-2181.
[17] Tai CJ, Li CL, Tai CJ, et al. Early viral entry assays for the identification and evaluation of antiviral compounds[J]. J Vis Exp, 2015, 105:e53124.
[18] Larson RA, Dai D, Hosack VT, et al. Identification of a broadspectrum arenavirus entry inhibitor[J]. J Virol, 2008, 82:10768-10775.
[19] Tani H, Iha K, Shimojima M, et al. Analysis of Lujo virus cell entry using pseudotype vesicular stomatitis virus[J]. J Virol, 2014, 88:7317-7330.
[20] Li S, Sun Z, Pryce R, et al. Acidic pH-induced conformations and LAMP1 binding of the Lassa virus glycoprotein spike[J]. PLoS Pathog, 2016, 12:e1005418.
[21] Shao J, Liang Y, Ly H. Human hemorrhagic fever causing arena viruses:molecular mechanisms contributing to virus virulence and disease pathogenesis[J]. Pathogens, 2015, 4:283-306.
[22] Igonet S, Vaney MC, Vonrhein C, et al. X-ray structure of the arenavirus glycoprotein GP2 in its postfusion hairpin conforma tion[J]. Proc Natl Acad Sci U S A, 2011, 108:19967-19972.
[23] Willard KA, Alston JT, Acciani M, et al. Identification of residues in Lassa virus glycoprotein subunit 2 that are critical for protein function[J]. Pathogens, 2018. DOI:10.3390/patho gens8010001.
[24] Wikipedia. Arenavirus[EB/OL]. https://en.wikipedia.org/wiki/Arenavirus.
[25] Bolken TC, Laquerre S, Zhang Y, et al. Identification and charac terization of potent small molecule inhibitor of hemorrhagic fever new world arenaviruses[J]. Antiviral Res, 2006, 69:86-97.
[26] Dias DA, Urban S, Roessner U. A historical overview of natural products in drug discovery[J]. Metabolites, 2012, 2:303-336.
[27] Zheng D, Han L, Huang X, et al. Natural products in clinical trials:antiparasitic, antiviral and neurological drugs[J]. Acta Pharm Sin (药学学报), 2007, 42:576-582.
[28] Galinis DL, Fuller RW, McKee TC, et al. Structure-activity modifications of the HIV-1 inhibitors (+)-calanolide A and (-)-calanolide B[J]. J Med Chem, 1996, 39:4507-4510.
[29] Ma X, Li L, Zhu T, et al. Phenylspirodrimanes with anti-HIV activity from the sponge-derived fungus Stachybotrys chartarum MXH-X73[J]. J Nat Prod, 2013, 76:2298-2306.
[30] Whitby K, Taylor D, Patel D, et al. Action of celgosivir (6Obutanoyl castanospermine) against the pestivirus BVDV:implica tions for the treatment of hepatitis C[J]. Antivir Chem Chemother, 2004, 15:141-151.
[31] Si L, Meng K, Tian Z, et al. Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes[J]. Sci Adv, 2018, 4:eaau8408.
[32] Williams C, Harborne J, Greenham J, et al. Variations in lipophilic and vacuolar flavonoids among European Pulicaria species[J]. Phytochemistry, 2003, 64:275-283.
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