药学学报, 2014, 49(12): 1631-1638
引用本文:
马琳琳, 蒋建东, 李玉环. 抗流感病毒药物宿主靶点的研究进展[J]. 药学学报, 2014, 49(12): 1631-1638.
MA Lin-lin, JIANG Jian-dong, LI Yu-huan. The recent advances in the host targets of anti-influenza drugs[J]. Acta Pharmaceutica Sinica, 2014, 49(12): 1631-1638.

抗流感病毒药物宿主靶点的研究进展
马琳琳1, 蒋建东1,2, 李玉环1
1. 中国医学科学院、北京协和医学院, 医药生物技术研究所, 北京 100050;
2. 中国医学科学院、北京协和医学院, 药物研究所, 北京 100050
摘要:
现有针对病毒靶点药物的广泛使用加速了耐药株的出现, 促进了对抗流感药物宿主靶点的研究与探索.流感病毒复制需要宿主细胞因子和细胞信号通路的参与, 因此干扰病毒与细胞之间的相互作用可以抑制流感病毒的复制; 同时流感病毒感染初期会引起宿主的天然免疫应答, 诱导调节宿主的天然免疫机制可以防御流感感染; 另外, 为了抑制流感感染后期引发的过度炎症反应, 需要具有抗炎作用的药物来抑制流感引起的免疫失调和组织损伤.因此, 针对流感病毒宿主靶点的药物研发, 为流感的防治带来新的希望.
关键词:    流感病毒      宿主靶点      流感复制      天然免疫     
The recent advances in the host targets of anti-influenza drugs
MA Lin-lin1, JIANG Jian-dong1,2, LI Yu-huan1
1. Institute of Medicinal Biotechnology, Beijing 100050, China;
2. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
The challenge of the emergence of drug-resistant influenza strains, which is caused by wide spread utilization of direct-acting antivirals (DAAs), accelerates the research and exploration towards host targeted agents. In contrast to DAAs targeting viral replication components, host targeted agents, which regulate host factors and pathways linked to viral replication, can interfere the replication of influenza. Additionally, the innate immune system is activated by influenza during the early stage of infection, so manipulating the innate immune response may prevent the viral infection. However, the excessive inflammatory response induced at the late phase of influenza infection would lead to severe tissue injures. Thus, it is very important to explore drugs with anti-inflammatory actions to suppress these immune imbalances and tissue injures. Here we overview the current progresses about host targets related to anti-influenza drugs.
Key words:    influenza virus    host target    influenza replication    innate immune response   
收稿日期: 2014-05-28
基金项目: "艾滋病和病毒性肝炎等重大传染病防治"科技重大专项资助项目(2012ZX10004501-004-001).
通讯作者: 李玉环
Email: yuhuanlibj@126.com
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参考文献:
[1] Zhang Q, Zhao QJ, Xiong RS, et al. Research progress of anti-influenza virus agents [J]. Acta Pharm Sin (药学学报), 2010, 45: 289-299.
[2] Sheu TG, Fry AM, Garten RJ, et al. Dual resistance to adamantanes and oseltamivir among seasonal influenza A (H1N1) viruses: 2008-2010 [J]. J Infect Dis, 2011, 203: 13-17.
[3] Baillie JK, Digard P. Influenza-time to target the host? [J]. N Engl J Med, 2013, 369: 191-193.
[4] Edinger TO, Pohl MO, Stertz S. Entry of influenza A virus: host factors and antiviral targets [J]. J Gen Virol, 2014, 95: 263-277.
[5] Müller KH, Kakkola L, Nagaraj AS, et al. Emerging cellular targets for influenza antiviral agents [J]. Trends Pharmacol Sci, 2012, 33: 89-99.
[6] Yamauchi Y, Boukari H, Banerjee I, et al. Histone deacetylase 8 is required for centrosome cohesion and influenza A virus entry [J]. PLoS Pathog, 2011, 7: e1002316.
[7] Huotari J, Meyer-Schaller N, Hubner M, et al. Cullin-3 regulates late endosome maturation [J]. Proc Natl Acad Sci USA, 2012, 109: 823-828.
[8] Bertram S, Glowacka I, Steffen I, et al. Novel insights into proteolytic cleavage of influenza virus hemagglutinin [J]. Rev Med Virol, 2010, 20: 298-310.
[9] He J, Sun E, Bujny MV, et al. Dual function of CD81 in influenza virus uncoating and budding [J]. PLoS Pathog, 2013, 9: e1003701.
[10] Widjaja I, de Vries E, Tscherne DM, et al. Inhibition of the ubiquitin-proteasome system affects influenza A virus infection at a postfusion step [J]. J Virol, 2010, 84: 9625-9631.
[11] Gabriel G, Klingel K, Otte A, et al. Differential use of importin-α isoforms governs cell tropism and host adaptation of influenza virus [J]. Nat Commun, 2011, 2: 156.
[12] König R, Stertz S, Zhou Y, et al. Human host factors required for influenza virus replication [J]. Nature, 2010, 463: 813- 817.
[13] Zhang J, Li G, Ye X. Cyclin T1/CDK9 interacts with influenza A virus polymerase and facilitates its association with cellular RNA polymerase II [J]. J Virol, 2010, 84: 12619- 12627.
[14] Guan Z, Liu D, Mi S, et al. Interaction of Hsp40 with influenza virus M2 protein: implications for PKR signaling pathway [J]. Protein Cell, 2010, 1: 944-955.
[15] Li G, Zhang J, Tong X, et al. Heat shock protein 70 inhibits the activity of influenza A virus ribonucleoprotein and blocks the replication of virus in vitro and in vivo [J]. PLoS One, 2011, 6: e16546.
[16] Zhang C, Yang Y, Zhou X, et al. The NS1 protein of influenza A virus interacts with heat shock protein Hsp90 in human alveolar basal epithelial cells: implication for virus-induced apoptosis [J]. Virol J, 2011, 8: 181.
[17] Kainov DE, Muller KH, Theisen LL, et al. Differential effects of NS1 proteins of human pandemic H1N1/2009, avian highly pathogenic H5N1, and low pathogenic H5N2 influenza A viruses on cellular pre-mRNA polyadenylation and mRNA translation [J]. J Biol Chem, 2011, 286: 7239-7247.
[18] Boivin S, Hart DJ. Interaction of the influenza A virus polymerase PB2 C-terminal region with importin alpha isoforms provides insights into host adaptation and polymerase assembly [J]. J Biol Chem, 2011, 286: 10439-10448.
[19] Kawaguchi A, Momose F, Nagata K. Replication-coupled and host factor-mediated encapsidation of the influenza virus genome by viral nucleoprotein [J]. J Virol, 2011, 85: 6197- 6204.
[20] Jorba N, Coloma R, Ortin J. Genetic trans-complementation establishes a new model for influenza virus RNA transcription and replication [J]. PLoS Pathog, 2009, 5: e1000462.
[21] Eisfeld AJ, Neumann G, Kawaoka Y. Human immunodeficiency virus rev-binding protein is essential for influenza a virus replication and promotes genome trafficking in late-stage infection [J]. J Virol, 2011, 85: 9588-9598.
[22] Chen J, Huang S, Chen Z. Human cellular protein nucleoporin hNup98 interacts with influenza A virus NS2/nuclear export protein and overexpression of its GLFG repeat domain can inhibit virus propagation [J]. J Gen Virol, 2010, 91: 2474- 2484.
[23] Watanabe K, Takizawa N, Noda S, et al. Hsc70 regulates the nuclear export but not the import of influenza viral RNP: a possible target for the development of anti-influenza virus drugs [J]. Drug Discov Ther, 2008, 2: 77-84.
[24] Amorim MJ, Bruce EA, Read EK, et al. A Rab11-and microtubule-dependent mechanism for cytoplasmic transport of influenza A virus viral RNA [J]. J Virol, 2011, 85: 4143- 4156.
[25] Bruce EA, Digard P, Stuart AD. The Rab11 pathway is required for influenza A virus budding and filament formation [J]. J Virol, 2010, 84: 5848-5859.
[26] Dai X, Zhang L, Hong T. Host cellular signaling induced by influenza virus [J]. Sci China Life Sci, 2011, 54: 68-74.
[27] Meliopoulos VA, Andersen LE, Birrer KF, et al. Host gene targets for novel influenza therapies elucidated by high-throughput RNA interference screens [J]. FASEB J, 2012, 26: 1372-1386.
[28] Droebner K, Pleschka S, Ludwig S, et al. Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo [J]. Antiviral Res, 2011, 92: 195-203.
[29] Hayden MS, Ghosh S. NF-kappaB, the first quarter-century: remarkable progress and outstanding questions [J]. Genes Dev, 2012, 26: 203-234.
[30] Pinto R, Herold S, Cakarova L, et al. Inhibition of influenza virus-induced NF-kappaB and Raf/MEK/ERK activation can reduce both virus titers and cytokine expression simultaneously in vitro and in vivo [J]. Antiviral Res, 2011, 92: 45-56.
[31] Hsu MJ, Wu CY, Chiang HH, et al. PI3K/Akt signaling mediated apoptosis blockage and viral gene expression in oral epithelial cells during herpes simplex virus infection [J]. Virus Res, 2010, 153: 36-43.
[32] Jackson D, Killip MJ, Galloway CS, et al. Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K) [J]. Virology, 2010, 396: 94-105.
[33] Lu X, Masic A, Li Y, et al. The PI3K/Akt pathway inhibits influenza A virus-induced Bax-mediated apoptosis by negatively regulating the JNK pathway via ASK1 [J]. J Gen Virol, 2010, 91: 1439-1449.
[34] Tripathi S, White MR, Hartshorn KL. The amazing innate immune response to influenza A virus infection [J]. Innate Immun, 2013, doi: 10.1177/1753425913508992.
[35] Ng WC, Tate MD, Brooks AG, et al. Soluble host defense lectins in innate immunity to influenza virus [J]. J Biomed Biotechnol, 2012, doi: 10.1155/2012/732191.
[36] Nicholls JM. The battle between influenza and the innate immune response in the human respiratory tract [J]. Infect Chemother, 2013, 45: 11-21.
[37] Pang IK, Iwasaki A. Inflammasomes as mediators of immunity against influenza virus [J]. Trends Immunol, 2011, 32: 34-41.
[38] van de Sandt CE, Kreijtz JH, Rimmelzwaan GF. Evasion of influenza A viruses from innate and adaptive immune responses [J]. Viruses, 2012, 4: 1438-1476.
[39] Munoz-Fontela C, Pazos M, Delgado I, et al. p53 serves as a host antiviral factor that enhances innate and adaptive immune responses to influenza A virus [J]. J Immunol, 2011, 187: 6428-6436.
[40] Paget C, Ivanov S, Fontaine J, et al. Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages [J]. J Biol Chem, 2012, 287: 8816- 8829.
[41] Herold S, Ludwig S, Pleschka S, et al. Apoptosis signaling in influenza virus propagation, innate host defense, and lung injury [J]. J Leukoc Biol, 2012, 92: 75-82.
[42] Lee SM, Gai WW, Cheung TK, et al. Antiviral effect of a selective COX-2 inhibitor on H5N1 infection in vitro [J]. Antiviral Res, 2011, 91: 330-334.
[43] Bode C, Graler MH. Immune regulation by sphingosine 1-phosphate and its receptors [J]. Arch Immunol Ther Exp, 2012, 60: 3-12.
[44] Graler MH. Targeting sphingosine 1-phosphate (S1P) levels and S1P receptor functions for therapeutic immune interventions [J]. Cell Physiol Biochem, 2010, 26: 79-86.
[45] Lee SM,Yen HL. Targeting the host or the virus: current and novel concepts for antiviral approaches against influenza virus infection [J]. Antiviral Res, 2012, 96: 391-404.
[46] Perdomo MC, Santos JE, Badinga L. Trans-10, cis-12 conjugated linoleic acid and the PPAR-γ agonist rosiglitazone attenuate lipopolysaccharide-induced TNF-α production by bovine immune cells [J]. Domest Anim Endocrinol, 2011, 41: 118-125.
[47] Pisetsky DS, Gauley J, Ullal AJ. HMGB1 and microparticles as mediators of the immune response to cell death [J]. Antioxid Redox Signal, 2011, 15: 2209-2219.
[48] Moisy D, Avilov SV, Jacob Y, et al. HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication [J]. J Virol, 2012, 86: 9122-9133.
[49] Hreggvidsdóttir HS, Lundberg AM, Aveberger AC, et al. High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor [J]. Mol Med, 2012, 18: 224- 230.
[50] Hsu AC, See HV, Hansbro PM, et al. Innate immunity to influenza in chronic airways diseases [J]. Respirology, 2012, 17: 1166-1175.
[51] Sun H, Sun Y, Pu J, et al. Comparative virus replication and host innate responses in human cells infected with three prevalent clades (2.3.4, 2.3.2, and 7) of highly pathogenic avian influenza H5N1 viruses [J]. J Virol, 2014, 88: 725- 729.
[52] Nguyen JT, Smee DF, Barnard DL, et al. Efficacy of combined therapy with amantadine, oseltamivir, and ribavirin in vivo against susceptible and amantadine-resistant influenza A viruses [J]. PLoS One, 2012, 7: e31006.