包头医学院公共卫生学院;传染病溯源预警与智能决策全国重点实验室中国疾病预防控制中心病毒病预防控制所国家卫生健康委员会生物安全重点实验室;内蒙古医科大学基础医学院微生物教研室;
本研究旨在探索吐根碱对人冠状病毒OC43(Human coronavirus OC43, HCoV-OC43)的作用时相和抗病毒机制。首先,在MRC-5细胞上建立了HCoV-OC43病毒的体外感染复制动力学曲线,测定了药物的EC50和CC50。结果表明吐根碱能够在感染早期有效地抑制HCoV-OC43病毒在MRC-5细胞中的复制。通过转录组分析,发现HCoV-OC43感染和吐根碱处理均导致宿主基因表达的紊乱,并且两者共同激活了抗病毒通路。吐根碱可能通过激活OASL、Mx1和IFIT2等抗病毒基因来增强宿主对病毒的抵抗能力。此外,吐根碱还可能通过抑制TMEM41B表达而进一步影响病毒复制过程。这些研究结果为深入探究吐根碱作为抗冠状病毒药物的机制和潜在靶点提供了重要线索。
252 | 0 | 196 |
下载次数 | 被引频次 | 阅读次数 |
[1] Cui J, Li F, Shi Z L. Origin and evolution of pathogenic coronaviruses[J]. Nat Rev Microbiol, 2019, 17(3):181-192. DOI:10. 1038/s41579-018-0118-9.
[2] King A. Two more coronaviruses may infect people[J].Science, 2021, 372(6545):893. DOI:10. 1126/science. 372. 6545. 893.
[3] Chen B, Tian E K, He B, et al. Overview of lethal human coronaviruses[J]. Signal Transduct Target Ther, 2020, 5(1):89. DOI:10. 1038/s41392-020-0190-2.
[4] Cele S, Jackson L, Khoury D S, et al. Omicron extensively but incompletely escapes Pfizer BNT162b2neutralization[J]. Nature, 2022, 602(7898):654-656.DOI:10. 1038/s41586-021-04387-1.
[5] Carre?o J M, Alshammary H, Tcheou J, et al. Activity of convalescent and vaccine serum against SARS-CoV-2Omicron[J]. Nature, 2022, 602(7898):682-688.DOI:10. 1038/s41586-022-04399-5.
[6] Valipour M. Different Aspects of emetine's capabilities as a highly potent SARS-CoV-2 inhibitor against COVID-19[J]. ACS Pharmacol Transl Sci, 2022, 5(6):387-399. DOI:10. 1021/acsptsci. 2c00045.
[7] Grollman A P. Structural basis for inhibition of protein synthesis by emetine and cycloheximide based on an analogy between ipecac alkaloids and glutarimide antibiotics[J]. Proc Natl Acad Sci U S A, 1966, 56(6):1867-1874. DOI:10. 1073/pnas. 56. 6. 1867.
[8] Grollman A P. Inhibitors of protein biosynthesis. V.Effects of emetine on protein and nucleic acid biosynthesis in HeLa cells[J]. J Biol Chem, 1968, 243(15):4089-4094.
[9] Foreman K E, Jesse J N, 3rd, Kuo P C, et al. Emetine dihydrochloride:a novel therapy for bladder cancer[J].J Urol, 2014, 191(2):502-509. DOI:10. 1016/j.juro. 2013. 09. 014.
[10]Khandelwal N, Chander Y, Rawat K D, et al. Emetine inhibits replication of RNA and DNA viruses without generating drug-resistant virus variants[J]. Antiviral Res, 2017, 144:196-204. DOI:10. 1016/j.antiviral. 2017. 06. 006.
[11]Shen L, Niu J, Wang C, et al. High-Throughput screening and identification of potent broad-spectrum inhibitors of coronaviruses[J/OL]. J Virol, 2019, 93(12)e00023-19. DOI:10. 1128/jvi. 00023-19.
[12]Fan S, Zhen Q, Chen C, et al. Clinical efficacy of lowdose emetine for patients with COVID-19:a real-world study[J]. J BioX Res, 2021, 4(2):53-59. DOI:10. 1097/jbr. 0000000000000076.
[13]Wang A, Sun Y, Liu Q, et al. Low dose of emetine as potential anti-SARS-CoV-2 virus therapy:preclinical in vitro inhibition and in vivo pharmacokinetic evidences[J]. Mol Biomed, 2020, 1(1):14. DOI:10. 1186/s43556-020-00018-9.
[14]Choy K T, Wong A Y, Kaewpreedee P, et al.Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro[J]. Antiviral Res, 2020, 178:104786. DOI:10. 1016/j.antiviral. 2020. 104786.
[15]Kumar R, Afsar M, Khandelwal N, et al. Emetine suppresses SARS-CoV-2 replication by inhibiting interaction of viral mRNA with eIF4E[J]. Antiviral Res, 2021, 189:105056. DOI:10. 1016/j.antiviral. 2021. 105056.
[16]Wang Z, Gerstein M, Snyder M. RNA-Seq:a revolutionary tool for transcriptomics[J]. Nat Rev Genet, 2009, 10(1):57-63. DOI:10. 1038/nrg2484.
[17]Hrdlickova R, Toloue M, Tian B. RNA-Seq methods for transcriptome analysis[J/OL]. Wiley Interdiscip Rev RNA, 2017, 8(1)10. 1002/wrna. 1364. DOI:10. 1002/wrna. 1364.
[18]Schirtzinger E E, Kim Y, Davis A S. Improving human coronavirus OC43(HCoV-OC43)research comparability in studies using HCoV-OC43 as a surrogate for SARS-CoV-2[J]. J Virol Methods, 2022,299:114317. DOI:10. 1016/j. jviromet. 2021. 114317.
[19]Peng Y, Du N, Lei Y, et al. Structures of the SARSCoV-2 nucleocapsid and their perspectives for drug design[J]. Embo j, 2020, 39(20):e105938. DOI:10. 15252/embj. 2020105938.
[20]Chen Y, Wang X, Shi H, et al. Montelukast inhibits HCoV-OC43 infection as a viral inactivator[J].Viruses, 2022, 14(5). DOI:10. 3390/v14050861.
[21]Niu P, Shen J, Zhu N, et al. Two-tube multiplex realtime reverse transcription PCR to detect six human coronaviruses[J]. Virol Sin, 2016, 31(1):85-88.DOI:10. 1007/s12250-015-3653-9.
[22]Roth R, Madhani H D, Garcia J F. Total RNA isolation and quantification of specific RNAs in fission yeast[J]. Methods Mol Biol, 2018, 1721:63-72. DOI:10. 1007/978-1-4939-7546-4_6.
[23]Mortazavi A, Williams B A, McCue K, et al. Mapping and quantifying mammalian transcriptomes by RNA-Seq[J]. Nat Methods, 2008, 5(7):621-628. DOI:10. 1038/nmeth. 1226.
[24]Kim D, Paggi J M, Park C, et al. Graph-based genome alignment and genotyping with HISAT2 and HISATgenotype[J]. Nat Biotechnol, 2019, 37(8):907-915.DOI:10. 1038/s41587-019-0201-4.
[25]Liao Y, Smyth G K, Shi W. featureCounts:an efficient general purpose program for assigning sequence reads to genomic features[J]. Bioinformatics, 2014, 30(7):923-930. DOI:10. 1093/bioinformatics/btt656.
[26]Love M I, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2[J]. Genome Biol, 2014, 15(12):550. DOI:10. 1186/s13059-014-0550-8.
[27]Ji M, Li M, Sun L, et al. VMP1 and TMEM41B are essential for DMV formation during β-coronavirus infection[J/OL]. J Cell Biol, 2022, 221(6)e202112081. DOI:10. 1083/jcb. 202112081.
[28]Baggen J, Vanstreels E, Jansen S, et al. Cellular host factors for SARS-CoV-2 infection[J]. Nat Microbiol,2021, 6(10):1219-1232. DOI:10. 1038/s41564-021-00958-0.
[29]Zhang Q, Sharma N R, Zheng Z M, et al. Viral regulation of RNA granules in infected Cells[J]. Virol Sin, 2019, 34(2):175-191. DOI:10. 1007/s12250-019-00122-3.
[30]Tang Q, Li S, Du L, et al. Emetine protects mice from enterovirus infection by inhibiting viral translation[J].Antiviral Res, 2020, 173:104650. DOI:10. 1016/j.antiviral. 2019. 104650.
[31]Mukhopadhyay R, Roy S, Venkatadri R, et al. Efficacy and mechanism of action of low dose emetine against human cytomegalovirus[J/OL]. PLoS Pathog, 2016,12(6):e1005717. DOI:10. 1371/journal.ppat. 1005717.
[32]Boon-Unge K, Yu Q, Zou T, et al. Emetine regulates the alternative splicing of Bcl-x through a protein phosphatase 1-dependent mechanism[J]. Chem Biol,2007, 14(12):1386-1392. DOI:10. 1016/j.chembiol. 2007. 11. 004.
[33]Han Y, Park S, Kinyua A W, et al. Emetine enhances the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of pancreatic cancer cells by downregulation of myeloid cell leukemia sequence-1protein[J]. Oncol Rep, 2014, 31(1):456-462. DOI:10. 3892/or. 2013. 2838.
[34]Schoggins J W, Rice C M. Interferon-stimulated genes and their antiviral effector functions[J]. Curr Opin Virol, 2011, 1(6):519-525. DOI:10. 1016/j.coviro. 2011. 10. 008.
[35]Schoggins J W, MacDuff D A, Imanaka N, et al. Panviral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity[J]. Nature, 2014, 505(7485):691-695. DOI:10. 1038/nature12862.
[36]Zhu J, Zhang Y, Ghosh A, et al. Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor[J]. Immunity, 2014, 40(6):936-948. DOI:10. 1016/j. immuni. 2014. 05. 007.
[37]Lee S A, Chang L C, Jung W, et al. OASL phase condensation induces amyloid-like fibrillation of RIPK3to promote virus-induced necroptosis[J]. Nat Cell Biol,2023, 25(1):92-107. DOI:10. 1038/s41556-022-01039-y.
[38]Zürcher T, Pavlovic J, Staeheli P. Mechanism of human MxA protein action:variants with changed antiviral properties[J]. Embo j, 1992, 11(4):1657-1661. DOI:10. 1002/j. 1460-2075. 1992. tb05212. x.
[39]Prentice E, McAuliffe J, Lu X, et al. Identification and characterization of severe acute respiratory syndrome coronavirus replicase proteins[J]. J Virol, 2004, 78(18):9977-9986. DOI:10. 1128/jvi. 78. 18. 9977-9986. 2004.
[40]Miao G, Zhao H, Li Y, et al. ORF3a of the COVID-19 virus SARS-CoV-2 blocks HOPS complex-mediated assembly of the SNARE complex required for autolysosome formation[J]. Dev Cell, 2021, 56(4):427-442. e425. DOI:10. 1016/j. devcel. 2020. 12. 010.
[41]Snijder E J, Limpens R, de Wilde A H, et al. A unifying structural and functional model of the coronavirus replication organelle:Tracking down RNA synthesis[J/OL]. PLoS Biol, 2020, 18(6):e3000715. DOI:10. 1371/journal. pbio. 3000715.
[42]Knoops K, Kikkert M, Worm S H, et al. SARScoronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum[J/OL].PLoS Biol, 2008, 6(9):e226. DOI:10. 1371/journal.pbio. 0060226.
[43]Hoffmann H H, Schneider W M, Rozen-Gagnon K, et al. TMEM41B is a pan-flavivirus host factor[J]. Cell,2021, 184(1):133-148. e120. DOI:10. 1016/j.cell. 2020. 12. 005.
基本信息:
DOI:10.13242/j.cnki.bingduxuebao.004515
中图分类号:R96
引用信息:
[1]李涵,张高倩,吴长城等.广谱抗病毒药物吐根碱抑制HCoV-OC43的转录组分析[J].病毒学报,2024,40(03):458-468.DOI:10.13242/j.cnki.bingduxuebao.004515.
基金信息:
国家重点研发计划(项目号:2023YFC3041500),题目:奥密克戎变异规律分析与防控研究;国家重点研发计划(项目号:2021YFA1201003),题目:抗病毒纳米药物的体内外功能评价; 国家自然科学基金(项目号:U21A20384),题目:基于PROTAC技术靶向降解SARS-CoV-2 Mpro蛋白的新型广谱抗冠状病毒药物的研发~~