Abstract
In the first part of this overview, we described the life cycle of the influenza virus and the pharmacological action of the currently available drugs. This second part provides an overview of the molecular mechanisms and targets of still-experimental drugs for the treatment and management of influenza.
Briefly, we can distinguish between compounds with anti-influenza activity that target influenza virus proteins or genes, and molecules that target host components that are essential for viral replication and propagation. These latter compounds have been developed quite recently. Among the first group, we will focus especially on hemagglutinin, M2 channel and neuraminidase inhibitors. The second group of compounds may pave the way for personalized treatment and influenza management. Combination therapies are also discussed.
In recent decades, few antiviral molecules against influenza virus infections have been available; this has conditioned their use during human and animal outbreaks. Indeed, during seasonal and pandemic outbreaks, antiviral drugs have usually been administered in monotherapy and, sometimes, in an uncontrolled manner to farm animals. This has led to the emergence of viral strains displaying resistance, especially to compounds of the amantadane family. For this reason, it is particularly important to develop new antiviral drugs against influenza viruses. Indeed, although vaccination is the most powerful means of mitigating the effects of influenza epidemics, antiviral drugs can be very useful, particularly in delaying the spread of new pandemic viruses, thereby enabling manufacturers to prepare large quantities of pandemic vaccine. In addition, antiviral drugs are particularly valuable in complicated cases of influenza, especially in hospitalized patients.
To write this overview, we mined various databases, including Embase, PubChem, DrugBank and Chemical Abstracts Service, and patent repositories.
References
Gasparini R, Amicizia D, Lai PL, et al. Compounds with anti- influenza activity: present and future of strategies for the op- timal treatment and management of influenza. Part I: influ- enza life-cycle and currently available drugs. J Prev Med Hyg 2014;55:69-85.
Müller KH, Kakkola L, Nagaraj AS, et al. Emerging cellular targets for influenza antiviral agents. Trends Pharmacol Sci 2012;33:89-99.
Planz O. Development of cellular signaling pathway in- hibitors as new antivirals against influenza. Antiviral Res 2013;98:457-68.
Embase. Accessible at http://www.elsevier.com/online-tools/ embase (last accessed: 16/07/2014).
PubChem. Accessible at http://www.ncbi.nlm.nih.gov/pcsub- stance/ (last accessed: 16/07/2014).
PubChem. Accessible at http://www.ncbi.nlm.nih.gov/pccom- pound/ (last accessed: 16/09/2014).
DrugBank. Accessible at http://www.drugbank.ca (last ac- cessed: 16/07/2014).
Chemical Abstracts Service. Accessible at https://scifinder.cas. org/ (last accessed: 16/07/2014).
Clinical trials registries. Accessible at https://clinicaltrials.gov/ ct2/home (last accessed: 16/07/2014).
Eyer L, Hruska K. Antiviral agents targeting the influenza vi- rus: a review and publication analysis. Veterinarni Medicina 2013;58:113-85.
CIRI-IT. Accessible at http://www.cirinet.it/jm/ (last accessed: 16/09/2014).
Pu JY, He L, Wu SY, et al. Anti-virus research of triterpenoids in licorice. Bing Du Xue Bao 2013;29:673-9.
Jia W, Wang C, Wang Y, et al. Qualitative and quantitative analysis of the major constituents in chinese medical prepara- tion Lianhua-Qingwen capsule by UPLC-DAD-QTOF-MS. Sci- entific World Journal 2015;2015:731-65.
Utsunomiya T, Kobayashi M, Pollard RB, et al. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob Agents Chemother 1997;41:551-6.
Fiore C, Eisenhut M, Krausse R, et al. Antiviral effects of Gly- cyrrhiza species. Phytother Res 2008;22:141-8.
Harada S. The broad anti-viral agent glycyrrhizin directly mod- ulates the fluidity of plasma membrane and HIV-1 envelope. Biochem J 2005;392:191-9.
Smirnov VS, Garshinina AV, Guseva VM, et al. The anti-viral activity of the complex glycyrrhizic acid-alpha-glutamyl-tryp- tophan against experimental lethal influenza infection in white mice caused by oseltamivir-resistant strain of the virus. Vopr Virusol 2013;58:19-26.
Smirnov VS, Zarubaev VV, Anfimov PM, et al. Effect of a com- bination of glutamyl-tryptophan and glycyrrhizic acid on the course of acute infection caused by influenza (H3H2) virus in mice. Vopr Virusol 2012;57:23-7.
Wolkerstorfer A, Kurz H, Bachhofner N, et al. Glycyrrhizin inhibits influenza A virus uptake into the cell. Antiviral Res 2009;83:171-8.
Michaelis M, Geiler J, Naczk P, et al. Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-in- flammatory cytokine and chemokine expression in human mac- rophages. Med Microbiol Immunol 2010;199:291-7
Michaelis M, Geiler J, Naczk P, et al. Glycyrrhizin exerts an- tioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expres- sion. PLoS One 2011;6:e19705.
Moisy D, Avilov SV, Jacob Y, et al. HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication. J Virol 2012;86:9122-33.
Stanetty C, Wolkerstorfer A, Amer H, et al. Synthesis and anti- viral activities of spacer-linked 1-thioglucuronide analogues of glycyrrhizin. Beilstein J Org Chem 2012;8:705-11.
Pompei R, Paghi L, Ingianni A, et al. Glycyrrhizic acid inhibits influenza virus growth in embryonated eggs. Microbiologica 1983;6:247-50.
Scherließ R, Ajmera A, Dennis M, et al. Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spray- dried and electron-beam sterilised vaccines in non-human pri- mates. Vaccine 2014;32:2231-40.
Song G, Yang S, Zhang W, et al. Discovery of the first se- ries of small molecule H5N1 entry inhibitors. J Med Chem 2009;52:7368-71.
Song W, Si L, Ji S, et al. Uralsaponins M-Y, antiviral triter- penoid saponins from the roots of Glycyrrhiza uralensis. J Nat Prod 2014;77:1632-43.
Song X, Chen J, Sakwiwatkul K, et al. Enhancement of immune responses to influenza vaccine (H3N2) by ginsenoside Re. Int Immunopharmacol 2010;10:351-6.
Barr IG, Mitchell GF. ISCOMs (immunostimulating complex- es): the first decade. Immunol Cell Biol 1996;74:8-25.
Liu H, Patil HP, de Vries-Idema J, et al. Enhancement of the immunogenicity and protective efficacy of a mucosal influenza subunit vaccine by the saponin adjuvant GPI-0100. PLoS One 2012;7:e52135.
Liu H, de Vries-Idema J, Ter Veer W, et al. Influenza virosomes supplemented with GPI-0100 adjuvant: a potent vaccine for- mulation for antigen dose sparing. Med Microbiol Immunol 2014;203:47-55.
Zhai L, Li Y, Wang W, et al. Enhancement of humoral immune responses to inactivated Newcastle disease and avian influenza vaccines by oral administration of ginseng stem-and-leaf sapo- nins in chickens. Poult Sci 2011;90:1955-9.
Sun H, He S, Shi M. Adjuvant-active fraction from Albizia ju- librissin saponins improves immune responses by inducing cy- tokine and chemokine at the site of injection. Int Immunophar- macol 2014;22:346-55.
Kazakova OB, Giniyatullina GV, Yamansarov EY, et al. Betu- lin and ursolic acid synthetic derivatives as inhibitors of Papil- loma virus. Bioorg Med Chem Lett 2010;20:4088-90.
Kazakova OB, Medvedeva NI, Baĭkova IP, et al. Synthesis of triterpenoid acylates - an effective reproduction inhibitors of influenza A (H1N1) and papilloma viruses. Bioorg Khim 2010;36:841-8.
Flekhter OB, Medvedeva NI, Kukovinets OS, et al. Synthesis and antiviral activity of lupane triterpenoids with modified cy- cle E. Bioorg Khim 2007;33:629-34.
Baltina LA, Flekhter OB, Nigmatullina LR, et al. Lupane triter- penes and derivatives with antiviral activity. Bioorg Med Chem Lett 2003;13:3549-52.
Grishko VV, Galaiko NV, Tolmacheva IA, et al. Functionali- zation, cyclization and antiviral activity of A-secotriterpenoids. Eur J Med Chem 2014;83:601-8.
Krumbiegel M, Dimitrov DS, Puri A, et al. Dextran sulfate in- hibits fusion of influenza virus and cells expressing influenza hemagglutinin with red blood cells. Biochim Biophys Acta 1992;1110:158-64.
Herrmann A, Korte T, Arnold K, et al. The influence of dextran sulfate on influenza A virus fusion with erythrocyte membranes. Antiviral Res 1992;19:295-311.
Lüscher-Mattli M, Glück R, Kempf C, et al. A comparative study of the effect of dextran sulfate on the fusion and the in vitro replication of influenza A and B, Semliki Forest, vesic- ular stomatitis, rabies, Sendai, and mumps virus. Arch Virol 1993;130:317-26.
Yamada H, Moriishi E, Haredy AM, et al. Influenza virus neu- raminidase contributes to the dextran sulfate-dependent sup- pressive replication of some influenza A virus strains. Antiviral Res 2012;96:344-52.
Yamada H, Nagao C, Haredy AM, et al. Dextran sulfate-resist- ant A/Puerto Rico/8/34 influenza virus is associated with the emergence of specific mutations in the neuraminidase glycopro- tein. Antiviral Res 2014;111:69-77.
Shkurupy VA, Potapova OV, Sharkova TV, et al. Experimental study of the efficiency of oxidized dextran for prevention of in- fluenza A/H5N1. Bull Exp Biol Med 2014;158:112-4.
Shkurupy VA, Potapova OV, Sharkova TV, et al. Effects of Preventive Administration of Oxidized Dextran on Liver Injury and Reparative Regeneration in Mice Infected with Influenza A/ H5N1 Virus. Bull Exp Biol Med 2015;158:483-8.
Potapova OV, Shkurupiy VA, Sharkova TV, et al. Preventive efficacy of oxidized dextran and pathomorphological processes in mouse lungs in avian influenza A/H5N1. Bull Exp Biol Med 2011;150:707-10.
De Clercq E. Highlights in the development of new antiviral agents. Mini Rev Med Chem 2002;2:163-75.
Bond S, Draffan AG, Fenner JE, et al. 1,2,3,9b-Tetrahydro-5H- imidazo,1-a]isoindol-5-ones as a new class of respiratory syn- cytial virus (RSV) fusion inhibitors. Part 2: identification of BTA9881 as a preclinical candidate. Bioorg Med Chem Lett 2015;25:976-81.
Weisman LE. Respiratory syncytial virus (RSV) prevention and treatment: past, present, and future. Cardiovasc Hematol Agents Med Chem 2009;7:223-33.
Guinea R, Carrasco L. Concanamycin A blocks influenza virus entry into cells under acidic conditions. FEBS Lett 1994;349:327-30.
Guinea R, Carrasco L. Concanamycin A: a powerful inhibitor of enveloped animal-virus entry into cells. Biochem Biophys Res Commun 1994;201:1270-8.
Guinea R, Carrasco L. Requirement for vacuolar proton-AT- Pase activity during entry of influenza virus into cells. J Virol 1995;69:2306-12.
Müller KH, Kainov DE, El Bakkouri K, et al. The proton trans- location domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections. Br J Pharmacol 2011;164:344-57
Yeganeh B, Ghavami S, Kroeker AL, et al. Suppression of influ- enza A virus replication in human lung epithelial cells by non- cytotoxic concentrations bafilomycin A1. Am J Physiol Lung Cell Mol Physiol 2015;308:L270-86.
Ochiai H, Sakai S, Hirabayashi T, et al. Inhibitory effect of ba- filomycin A1, a specific inhibitor of vacuolar-type proton pump, on the growth of influenza A and B viruses in MDCK cells. An- tiviral Res 1995;27:425-30.
Bimbo LM, Denisova OV, Mäkilä E, et al. Inhibition of influ- enza A virus infection in vitro by saliphenylhalamide-loaded porous silicon nanoparticles. ACS Nano 2013;7:6884-93.
Paton NI, Lee L, Xu Y, et al. Chloroquine for influenza pre- vention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis 2011;11:677-83.
Savarino A. Use of chloroquine in viral diseases. Lancet Infect Dis 2011;11:653-4.
Ooi EE, Chew JS, Loh JP, et al. In vitro inhibition of human influenza A virus replication by chloroquine. Virol J 2006;3:39.
Di Trani L, Savarino A, Campitelli L, et al. Different pH re- quirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses. Virol J 2007;4:39.
Vigerust DJ, McCullers JA. Chloroquine is effective against in- fluenza A virus in vitro but not in vivo. Influenza Other Respir Viruses 2007;1:189-92.
Yan Y, Zou Z, Sun Y, et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infec- tion in an animal model. Cell Res 2013;23:300-2.
Garulli B, Di Mario G, Sciaraffia E, et al. Enhancement of T cell-mediated immune responses to whole inactivated in- fluenza virus by chloroquine treatment in vivo. Vaccine 2013;31:1717-24.
Wu L, Dai J, Zhao X, et al. Chloroquine enhances replication of influenza A virus A/WSN/33 (H1N1) in dose-, time-, and MOI- dependent manners in human lung epithelial cells A549. J Med Virol 2015, in press.
De Clercq E. A Cutting-edge view on the current state of antivi- ral drug development. Med Res Rev 2013;33:1249–1277.
Blaising J, Lévy PL, Gondeau C, et al. Silibinin inhibits hepati- tis C virus entry into hepatocytes by hindering clathrin-depend- ent trafficking. Cell Microbiol 2013;15:1866-82.
Dai JP, Wu LQ, Li R, et al. Identification of 23-(s)-2-amino- 3-phenylpropanoyl-silybin as an antiviral agent for influenza A virus infection in vitro and in vivo. Antimicrob Agents Chem- other 2013;57:4433-43.
Gazák R, Purchartová K, Marhol P, et al. Antioxidant and anti- viral activities of silybin fatty acid conjugates. Eur J Med Chem 2010;45:1059-67.
Garozzo A, Timpanaro R, Bisignano B, et al. In vitro antiviral activity of Melaleuca alternifolia essential oil. Lett Appl Micro- biol 2009;49:806-8.
Garozzo A, Timpanaro R, Stivala A, et al. Activity of Melaleuca alternifolia (tea tree) oil on Influenza virus A/PR/8: study on the mechanism of action. Antiviral Res 2011;89:83-8.
Li X, Duan S, Chu C, et al. Melaleuca alternifolia concentrate inhibits in vitro entry of influenza virus into host cells. Mol- ecules 2013;18:9550-66.
Mantil E, Daly G, Avis TJ. Effect of tea tree (Melaleuca alterni- folia) oil as a natural antimicrobial agent in lipophilic formula- tions. Can J Microbiol 2015;61:82-8.
He J, Qi WB, Wang L, et al. Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1. In- fluenza Other Respir Viruses 2013;7:922-31.
Aggarwal BB, Deb L, Prasad S. Curcumin differs from tetrahy- drocurcumin for molecular targets, signaling pathways and cel- lular responses. Molecules 2014;20:185-205.
Chen TY, Chen DY, Wen HW, et al. Inhibition of enveloped viruses infectivity by curcumin. PLoS One 2013;8:e62482.
Shuto T. Regulation of expression, function, and inflamma- tory responses of innate immune receptor Toll-like receptor-2 (TLR2) during inflammatory responses against infection. Yaku- gaku Zasshi 2013;133:1401-9.
Kim K, Kim KH, Kim HY, et al. Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway. FEBS Lett. 2010;584:707-12.
Rajput N, Naeem M, Ali S, et al. The effect of dietary supple- mentation with the natural carotenoids curcumin and lutein on broiler pigmentation and immunity. Poult Sci 2013;92:1177-85.
Ou JL, Mizushina Y, Wang SY, et al. Structure-activity rela- tionship analysis of curcumin analogues on anti-influenza virus activity. FEBS J 2013;280:5829-40.
Haasbach E, Hartmayer C, Hettler A, et al. Antiviral activ- ity of Ladania067, an extract from wild black currant leaves against influenza A virus in vitro and in vivo. Front Microbiol 2014;5:171.
Ehrhardt C, Dudek SE, Holzberg M, et al. A plant extract of Ribes nigrum folium possesses anti-influenza virus activity in vitro and in vivo by preventing virus entry to host cells. PLoS One 2013;8:e63657.
Yokomizo K, Miyamoto Y, Nagao K, et al. Fattiviracin A1, a novel antiviral agent produced by Streptomyces microflavus strain No. 2445. II. Biological properties. J Antibiot (Tokyo) 1998;51:1035-9.
Habib ES, Yokomizo K, Nagao K, et al. Antiviral activity of fattiviracin FV-8 against human immunodeficiency virus type 1 (HIV-1). Biosci Biotechnol Biochem 2001;65:683-5.
Tanaka T, Ikeda T, Kaku M, et al. A new lignan glycoside and phenylethanoid glycosides from Strobilanthes cusia BREMEK. Chem Pharm Bull (Tokyo) 2004;52:1242-5.
Uyeda M. Metabolites produced by actinomycetes-anti- viral antibiotics and enzyme inhibitors. Yakugaku Zasshi 2004;124:469-79.
Liao Q, Qian Z, Liu R, et al. Germacrone inhibits early stages of influenza virus infection. Antiviral Res 2013;100:578-88.
Denisova OV, Söderholm S, Virtanen S, et al. Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro. An- timicrob Agents Chemother 2014;58:3689-96.
Hirata N, Suizu F, Matsuda-Lennikov M, et al. Inhibition of Akt kinase activity suppresses entryand replication of influenza vi- rus. Biochem Biophys Res Commun 2014;450:891-8.
Hsieh CF, Lo CW, Liu CH, et al. Mechanism by which ma-xing- shi-gan-tang inhibits the entry of influenza virus. J Ethnophar- macol 2012;143:57-67.
Murray JL, McDonald NJ, Sheng J, et al. Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR path- way member identified by gene-trap insertional mutagenesis. Antivir Chem Chemother 2012;22:205-15.
Chan RW, Chan MC, Wong AC, et al. DAS181 inhibits H5N1 influenza virus infection of human lung tissues. Antimicrob Agents Chemother 2009;53:3935-41.
Triana-Baltzer GB, Gubareva LV, Nicholls JM, et al. Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein. PLoS One 2009;4:e7788.
Triana-Baltzer GB, Gubareva LV, Klimov AI, et al. Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein. PLoS One 2009;4:e7838.
Triana-Baltzer GB, Babizki M, Chan MC, et al. DAS181, a sial- idase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analy- sis. J Antimicrob Chemother 2010;65:275-84.
Moss RB, Hansen C, Sanders RL, et al. A phase II study of DAS181, a novel host directed antiviral for the treatment of in- fluenza infection. J Infect Dis 2012;206:1844-51.
Ison MG. Expanding the armamentarium against respiratory viral infections: DAS181. J Infect Dis 2012;206:1806-8.
Zhang H. DAS181 and H5N1 virus infection. J Infect Dis 2009;199:1250, author reply 1250-1.
Moscona A, Porotto M, Palmer S, et al. A recombinant sialidase fusion protein effectively inhibits human parainfluenza viral in- fection in vitro and in vivo. J Infect Dis 2010;202:234-41.
Jones BG, Hayden RT, Hurwitz JL. Inhibition of primary clinical isolates of human parainfluenza virus by DAS181 in cell culture and in a cotton rat model. Antiviral Res 2013;100:562-6.
Malakhov MP, Aschenbrenner LM, Smee DF, et al. Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection. Antimicrob Agents Chemother 2006;50:1470-9.
Hayden F. Developing new antiviral agents for influenza treat- ment: what does the future hold? Clin Infect Dis 2009;48 Suppl 1:S3-13.
Belser JA, Lu X, Szretter KJ, et al. DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection. J Infect Dis 2007;196:1493-9.
Marjuki H, Mishin VP, Chesnokov AP, et al. An investigational antiviral drug, DAS181, effectively inhibits replication of zo- onotic influenza A virus subtype H7N9 and protects mice from lethality. J Infect Dis 2014;210:435-40.
Zhu L, Li Y, Li S, et al. Inhibition of influenza A virus (H1N1) fusion by benzenesulfonamide derivatives targeting viral he- magglutinin. PLoS One 2011;6:e29120.
Hsieh HP, Hsu JT. Strategies of development of antiviral agents directed against influenza virus replication. Curr Pharm Des 2007;13:3531-42.
Shigeta S. Current status of research and development for anti-influenza virus drugs--chemotherapy for influenza. Nihon Rinsho 1997;55:2758-64.
Luo G, Torri A, Harte WE, et al. Molecular mechanism under- lying the action of a novel fusion inhibitor of influenza A virus. J Virol 1997;71:4062-70.
Vichkanova SA, Oĭfa AI, Goriunova LV. Antiviral properties of gossypol in experimental influenza pneumonia. Antibiotiki 1970;15:1071-3.
Krylov VF. Treatment of patients with influenza. Ter Arkh 1975;47:49-55.
Yang J, Zhang F, Li J, et al. Synthesis and antiviral activi- ties of novel gossypol derivatives. Bioorg Med Chem Lett 2012;22:1415-20.
Yang J, Chen G, Li LL, et al. Synthesis and anti-H5N1 activ- ity of chiral gossypol derivatives and its analogs implicated by a viral entry blocking mechanism. Bioorg Med Chem Lett 2013;23:2619-23.
Jones JC, Turpin EA, Bultmann H, et al. Inhibition of influenza virus infection by a novel antiviral peptide that targets viral at- tachment to cells. J Virol 2006;80:11960-7.
Altmann SE, Brandt CR, Jahrling PB, et al. Antiviral activity of the EB peptide against zoonotic poxviruses. Virol J 2012;9:6.
Nicol MQ, Ligertwood Y, Bacon MN, et al. A novel family of peptides with potent activity against influenza A viruses. J Gen Virol 2012;93:980-6.
Rajik M, Jahanshiri F, Omar AR, et al. Identification and char- acterisation of a novel anti-viral peptide against avian influ- enza virus H9N2. Virol J 2009;6:74.
Matsubara T. Potential of peptides as inhibitors and mimo- topes: selection of carbohydrate-mimetic peptides from phage display libraries. J Nucleic Acids. 2012;2012:740982.
Selman L, Hansen S. Structure and function of collectin liver 1 (CL-L1) and collectin 11 (CL-11, CL-K1). Immunobiology 2012;217:851-63.
Ling MT, Tu W, Han Y, et al. Mannose-binding lectin contrib- utes to deleterious inflammatory response in pandemic H1N1 and avian H9N2 infection. J Infect Dis 2012;205:44-53.
Dec M, Wernicki A. Conglutinin, CL-43 and CL-46-three bo- vine collectins. Pol J Vet Sci 2006;9:265-75.
Kawai T, Kase T, Suzuki Y, et al. Anti-influenza A virus ac- tivities of mannan-binding lectins and bovine conglutinin. J Vet Med Sci 2007;69:221-4.
Malhotra R, Haurum JS, Thiel S, et al. Binding of human collectins (SP-A and MBP) to influenza virus. Biochem J 1994;304:455-61.
Hartshorn KL, Sastry K, Brown D, et al. Conglutinin acts as an opsonin for influenza A viruses. J Immunol 1993;151:6265-73.
Verma A, White M, Vathipadiekal V, et al. Human H-ficolin in- hibits replication of seasonal and pandemic influenza A viruses. J Immunol 2012;189:2478-87.
Pan Q, Chen H, Wang F, et al. L-ficolin binds to the glyco- proteins hemagglutinin and neuraminidase and inhibits influ- enza A virus infection both in vitro and in vivo. J Innate Immun 2012;4:312-24.
Chang WC, Hartshorn KL, White MR, et al. Recombinant chi- meric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with man- nose-binding lectin. Biochem Pharmacol 2011;81:388-95.
Gordts SC, Renders M, Férir G, et al. NICTABA and UDA, two GlcNAc-binding lectins with unique antiviral activity profiles. J Antimicrob Chemother 2015, in press.
Pustylnikov S, Sagar D, Jain P, et al. Targeting the C-type lec- tins-mediated host-pathogen interactions with dextran. J Pharm Pharm Sci 2014;17:371-92.
Morita M, Kuba K, Ichikawa A, et al. The lipid mediator pro- tectin D1 inhibits influenza virus replication and improves se- vere influenza. Cell 2013;153:112-25.
Zhang C, Xu Y, Jia L, et al. A new therapeutic strategy for lung tissue injury induced by influenza with CR2 targeting comple- ment inhibitor. Virol J 2010;7:30.
Imai Y. Role of omega-3 PUFA-derived mediators, the pro- tectins, in influenza virus infection. Biochim Biophys Acta 2015;1851:496-502.
Takahashi M, Mori S, Shigeta S, et al. Role of MBL-associated serine protease (MASP) on activation of the lectin complement pathway. Adv Exp Med Biol. 2007;598:93-104.
Smee DF, Bailey KW, Wong MH, et al. Treatment of influenza A (H1N1) virus infections in mice and ferrets with cyanovirin- N. Antiviral Res 2008;80:266-71.
O’Keefe BR, Smee DF, Turpin JA, et al. Potent anti-influenza activity of cyanovirin-N and interactions with viral hemaggluti- nin. Antimicrob Agents Chemother 2003;47:2518-25.
Miyamoto D, Hasegawa S, Sriwilaijaroen N, et al. Clarithro- mycin inhibits progeny virus production from human influenza virus-infected host cells. Biol Pharm Bull 2008;31:217-22.
Yamaya M, Shinya K, Hatachi Y, et al. Clarithromycin inhibits type a seasonal influenza virus infection in human airway epi- thelial cells. J Pharmacol Exp Ther 2010;333:81-90.
Ghendon Y, Markushin S, Heider H, et al. Haemagglutinin of influenza A virus is a target for the antiviral effect of Norakin. J Gen Virol 1986;67:1115-22.
Ott S, Wunderli-Allenspach H. Effect of the virostatic No- rakin (triperiden) on influenza virus activities. Antiviral Res 1994;24:37-42.
Presber HW, Schroeder C, Hegenscheid B, et al. Antiviral activ- ity of Norakin (triperiden) and related anticholinergic antipar- kinsonism drugs. Acta Virol 1984;28:501-7.
Heider H, Markushin S, Schroeder C, Ghendon Y. The influ- ence of Norakin on the reproduction of influenza A and B vi- ruses. Arch Virol 1985;86:283-90.
Schroeder C, Heider H, Hegenscheid B, et al. The anticholiner- gic anti-Parkinson drug Norakin selectively inhibits influenza virus replication. Antiviral Res 1985;(Suppl 1):95-9.
Prösch S, Heider H, Schroeder C, et al. Mutations in the he- magglutinin gene associated with influenza virus resistance to norakin. Arch Virol 1988;102:125-9.
Prösch S, Heider H, Schroeder C, et al. Mapping mutations in in- fluenza A virus resistant to norakin. FEBS Lett 1990;267:19-21.
Klimov AI, Markushin SG, Prösch S, et al. Relation be- tween drug resistance and antigenicity among norakin-re- sistant mutants of influenza A (fowl plague) virus. Arch Virol 1992;124:147-55.
Markushin SG, Ginzburg VP, Khaĭder AM, et al. Factors that cause a change in the antigenic structure of of the influenza virus hemagglutinin. Vopr Virusol 1992;37:196-9.
Oka M, Ishiwata Y, Iwata N, et al. Synthesis and anti-influenza virus activity of tricyclic compounds with a unique amine moi- ety. Chem Pharm Bull (Tokyo) 2001;49:379-83.
Rossignol JF. Nitazoxanide. A first-in-class broad-spectrum an- tiviral agent. Antiviral Res 2014, in press.
Ashiru O, Howe JD, Butters TD. Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca(2+) stores. Virology 2014;462-463:135-48.
Belardo G, Cenciarelli O, La Frazia S, et al. Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro. Antimicrob Agents Chemother 2015;59:1061-9.
Täubel J, Lorch U, Rossignol JF, et al. Analyzing the relation- ship of QT interval and exposure to nitazoxanide, a prospective candidate for influenza antiviral therapy – A formal TQT study. J Clin Pharmacol 2014;54:987-94.
Haffizulla J, Hartman A, Hoppers M, et al. Effect of nitazoxa- nide in adults and adolescents with acute uncomplicated influ- enza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 2014;14:609-18.
Ashton LV, Callan RL, Rao S, et al. In vitro susceptibility of ca- nine influenza A (H3N8) virus to nitazoxanide and tizoxanide. Vet Med Int 2010;2010.
Ulyanova V, Vershinina V, Ilinskaya O. Barnase and binase: twins with distinct fates. FEBS J 2011;278:3633-43.
Shah Mahmud R, Ilinskaya ON. Antiviral Activity of Binase against the Pandemic Influenza A (H1N1) Virus. Acta Naturae 2013;5:44-51.
Sato Y, Hirayama M, Morimoto K, et al. High mannose-binding lectin with preference for the cluster of alpha1-2-mannose from the green alga Boodlea coacta is a potent entry inhibitor of HIV-1 and influenza viruses. J Biol Chem 2011;286:19446-58.
Savov VM, Galabov AS, Tantcheva LP, et al. Effects of rutin and quercetin on monooxygenase activities in experimental in- fluenza virus infection. Exp Toxicol Pathol 2006;58:59-64.
Davis JM, Murphy EA, McClellan JL, et al. Quercetin reduces susceptibility to influenza infection following stressful exercise. Am J Physiol Regul Integr Comp Physiol 2008;295:R505-9.
Choi HJ, Song JH, Park KS, et al. Inhibitory effects of quercetin 3-rhamnoside on influenza A virus replication. Eur J Pharm Sci 2009;37:329-33.
Kumar P, Khanna M, Srivastava V, et al. Effect of quercetin supplementation on lung antioxidants after experimental influ- enza virus infection. Exp Lung Res 2005;31:449-59.
Raju TA, Lakshmi AN, Anand T, et al. Protective effects of quercetin during influenza virus-induced oxidative stress. Asia Pac J Clin Nutr 2000;9:314-7.
Friel H, Lederman H. A nutritional supplement formula for influenza A (H5N1) infection in humans. Med Hypotheses 2006;67:578-87.
Eşanu V, Prahoveanu E, Crişan I, et al. The effect of an aque- ous propolis extract, of rutin and of a rutin-quercetin mixture on experimental influenza virus infection in mice. Virologie 1981;32:213-5.
Chang SS, Huang HJ, Chen CY. Two birds with one stone? Pos- sible dual-targeting H1N1 inhibitors from traditional Chinese medicine. PLoS Comput Biol 2011;7:e1002315.
Chang TT, Sun MF, Chen HY, et al. Screening from the world’s largest TCM database against H1N1 virus. J Biomol Struct Dyn 2011;28:773-86.
Nakayama M, Suzuki K, Toda M, et al. Inhibition of the in- fectivity of influenza virus by tea polyphenols. Antiviral Res 1993;21:289-99.
Yang ZF, Bai LP, Huang WB, et al. Comparison of in vitro antiviral activity of tea polyphenols against influenza A and B viruses and structure-activity relationship analysis. Fitoterapia 2014;93:47-53.
Zu M, Yang F, Zhou W, et al. In vitro anti-influenza virus and anti-inflammatory activities of theaflavin derivatives. Antiviral Res 2012;94:217-24.
Hayden FG, Aoki FY. Amantadine, rimatadine, and related agents. In: Barriere SL, editor. Antimicrobial Therapy and Vac- cines. Baltimore: Williams & Williams 1999, pp 1344-1365.
Wang C, Takeuchi K, Pinto LH, et al. Ion channel activity of in- fluenza A virus M2 protein: characterization of the amantadine block. J Virol 1993;675585-94.
Ruigrok RW, Hirst EM, Hay AJ. The specific inhibition of in- fluenza A virus maturation by amantadine: an electron micro- scopic examination. J Gen Virol 1991;72:191-4.
Sheu TG, Fry AM, Garten RJ, et al. Dual resistance to ada- mantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008-2010. J Infect Dis 2011;203:13-7.
Smirnova TD, Danilenko DM, Eropkin MIu, et al. Influence of rimantadine, ribavirine and triazavirine on influenza A virus replication in human monolayer and lymphoblastoid cell lines. Antibiot Khimioter 2011;56:11-6.
Karpenko I, Deev S, Kiselev O, et al. Antiviral properties, me- tabolism, and pharmacokinetics of a novel azolo-1,2,4-triazine- derived inhibitor of influenza A and B virus replication. Antimi- crob Agents Chemother 2010;54:2017-22.
Tanner JA, Zheng BJ, Zhou J, et al. The adamantane-derived bananins are potent inhibitors of the helicase activities and rep- lication of SARS coronavirus. Chem Biol 2005;12:303-11.
Moorthy NS, Poongavanam V, Pratheepa V. Viral M2 ion chan- nel protein: a promising target for anti-influenza drug discov- ery. Mini Rev Med Chem 2014;14:819-30.
Rey-Carrizo M, Torres E, Ma C, et al. 3-Azatetracyc- lo.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type in- hibitors of the M2 ion channel of influenza A virus to deriva- tives with potent activity against the V27A mutant. J Med Chem 2013;56:9265-74.
Wang J, Wu Y, Ma C, et al. Structure and inhibition of the drug- resistant S31N mutant of the M2 ion channel of influenza A vi- rus. Proc Natl Acad Sci U S A 2013;110:1315-20.
Wang J, Ma C, Wang J, et al. Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N, of the M2 proton channel from influenza A virus. J Med Chem 2013;56:2804-12.
Gasparini R, Lai PL, Casabona F, et al. Do the omeprazole fam- ily compounds exert a protective effect against influenza-like illness? BMC Infect Dis 2014;14:297.
Bozdaganyan M, Orekhov P, Bragazzi NL, et al. Docking and molecular dynamics (MD) simulations in potential drugs dis- covery: an application to influenza virus M2 protein. Am J Bio- chem Biotechnol 2014;10:180-88.
3C9J. The Crystal structure of Transmembrane domain of M2 protein and Amantadine complex. Accesible at http://www. rcsb.org/pdb/explore.do?structureId=3c9j.
Long J, Wright E, Molesti E, et al. Antiviral therapies against Ebola and other emerging viral diseases using existing medi- cines that block virus entry. F1000Research 2015;4:30.
Bachrach U, Don S. Inactivation of influenza and New- castle disease viruses by oxidized spermine. Isr J Med Sci 1970;6:435-7.
Bachrach U. Antiviral activity of oxidized polyamines. Amino Acids 2007;33:267-72.
Lin TI, Heider H, Schroeder C. Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein. J Gen Virol 1997;78:767-74.
Even-Or O, Samira S, Rochlin E, et al. Immunogenicity, protec- tive efficacy and mechanism of novel CCS adjuvanted influenza vaccine. Vaccine 2010;28:6527-41.
Even-Or O, Joseph A, Itskovitz-Cooper N, et al. A new intrana- sal influenza vaccine based on a novel polycationic lipid-cera- mide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity. Vaccine 2011;29:2474-86.
Fytas C, Kolocouris A, Fytas G, et al. Influence of an ad- ditional amino group on the potency of aminoadamantanes against influenza virus A. II - Synthesis of spiropiperazines and in vitro activity against influenza A H3N2 virus. Bioorg Chem 2010;38:247-51.
Zhao X, Jie Y, Rosenberg MR, et al. Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel in- hibitors. Antiviral Res 2012;96:91-9.
Serkedjieva J, Manolova N, Bankova V. Anti-influenza virus effect of some propolis constituents and their analogues (esters of substituted cinnamic acids). J Nat Prod 1992;55:294-302.
Kesel AJ. Synthesis of novel test compounds for antiviral chem- otherapy of severe acute respiratory syndrome (SARS). Curr Med Chem 2005;12:2095-162.
Iwai A, Shiozaki T, Miyazaki T. Relevance of signaling mol- ecules for apoptosis induction on influenza A virus replication. Biochem Biophys Res Commun 2013;441:531-7.
Jurgeit A, McDowell R, Moese S, et al. Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral ef- fects. PLoS Pathog 2012;8:e1002976.
Krátký M, Vinšová J. Antiviral activity of substituted salicylani- lides – a review. Mini Rev Med Chem 2011;11:956-67.
Russell RJ, Kerry PS, Stevens DJ, et al. Structure of influenza hemagglutinin in complex with an inhibitor of membrane fu- sion. Proc Natl Acad Sci U S A 2008;105:17736-41.
Hosoya M, Matsuyama S, Baba M, et al. Effects of protease inhibitors on replication of various myxoviruses. Antimicrob Agents Chemother 1992;36:1432-6.
Bahgat MM, Blazejewska P, Schughart K. Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection. Virol J 2011;8:27.
Hamilton BS, Chung C, Cyphers SY, et al. Inhibition of in- fluenza virus infection and hemagglutinin cleavage by the protease inhibitor HAI-2. Biochem Biophys Res Commun 2014;450:1070-5.
Lee MG, Kim KH, Park KY, et al. Evaluation of anti-influenza effects of camostat in mice infected with non-adapted human influenza viruses. Arch Virol 1996;141:1979-89.
Puzis LE, Lozitsky VP. Action of epsilon-aminocaproic acid on the proteolysis system during experimental influenza in mice. Acta Virol 1988;32:515-21.
Compounds with anti-influenza aCtivity: present and future of strategies for the optimal treatment and management of influenza
Tashiro M, Klenk HD, Rott R. Inhibitory effect of a pro- tease inhibitor, leupeptin, on the development of influenza pneumonia, mediated by concomitant bacteria. J Gen Virol 1987;68:2039-41.
Zhirnov OP, Klenk HD, Wright PF. Aprotinin and similar protease inhibitors as drugs against influenza. Antiviral Res 2011;92:27-36.
Zhou Y, Wu C, Zhao L, et al. Exploring the early stages of the pH-induced conformational change of influenza hemagglutinin. Proteins 2014;82:2412-28.
Leikina E, Delanoe-Ayari H, Melikov K, et al. Carbohydrate- binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat Immunol 2005;6:995-1001.
Streeter DG, Witkowski JT, Khare GP, et al. Mechanism of ac- tion of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Vi- razole), a new broad-spectrum antiviral agent. Proc Natl Acad Sci U S A 1973;70:1174-8.
Crotty S, Cameron C, Andino R. Ribavirin’s antiviral mech- anism of action: lethal mutagenesis? J Mol Med (Berl) 2002;80:86-95.
Chan-Tack KM, Murray JS, Birnkrant DB. Use of ribavirin to treat influenza. N Engl J Med 2009;361:1713-4.
Gangemi JD, Nachtigal M, Barnhart D, et al. Therapeutic ef- ficacy of liposome-encapsulated ribavirin and muramyl tripep- tide in experimental infection with influenza or herpes simplex virus. J Infect Dis 1987;155:510-7.
Smee DF, Hurst BL, Day CW, et al. Influenza Virus H1N1 inhi- bition by serine protease inhibitor (serpin) antithrombin III. Int Trends Immun 2014;2:83-86.
Stoller JK, Lacbawan FL, Aboussouan LS. Alpha-1 Antitrypsin Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al, edi- tors. GeneReviews ® [Internet]. Seattle: University of Washing- ton, 1993-2014. 2006 Oct 27 [updated 2014 May 01].
Campos MA, Alazemi S, Zhang G, et al. Influenza vaccina- tion in subjects with alpha1-antitrypsin deficiency. Chest 2008;133:49-55.
Yagi S, Ono J, Yoshimoto J, et al. Development of anti-influ- enza virus drugs I: improvement of oral absorption and in vivo anti-influenza activity of Stachyflin and its derivatives. Pharm Res 1999;16:1041-6.
Yoshimoto J, Yagi S, Ono J, et al. Development of anti-influ- enza drugs: II. Improvement of oral and intranasal absorption and the anti-influenza activity of stachyflin derivatives. J Pharm Pharmacol 2000;52:1247-55.
Minagawa K, Kouzuki S, Yoshimoto J, et al. Stachyflin and ace- tylstachyflin, novel anti-influenza A virus substances, produced by Stachybotrys sp. RF-7260. I. Isolation, structure elucidation and biological activities. J Antibiot (Tokyo) 2002;55:155-64.
Minagawa K, Kouzuki S, Kamigauchi T. Stachyflin and acetyl- stachyflin, novel anti-influenza A virus substances, produced by Stachybotrys sp. RF-7260. II. Synthesis and preliminary struc- ture-activity relationships of stachyflin derivatives. J Antibiot (Tokyo) 2002;55:165-71.
Motohashi Y, Igarashi M, Okamatsu M, et al Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes. Virol J 2013;10:118.
Watanabe K, Sakurai J, Abe H, et al. Total synthesis of (+)-stachyflin: a potential anti-influenza A virus agent. Chem Commun (Camb) 2010;46:4055-7.
Nakatani M, Nakamura M, Suzuki A, et al. A new strategy to- ward the total synthesis of stachyflin, a potent anti-influenza A virus agent: concise route to the tetracyclic core structure. Org Lett 2002;4:4483-6.
Combrink KD, Gulgeze HB, Yu KL, et al. Salicylamide in- hibitors of influenza virus fusion. Bioorg Med Chem Lett 2000;10:1649-52.
Zhu L, Li Y, Li S, et al. Inhibition of influenza A virus (H1N1) fusion by benzenesulfonamide derivatives targeting viral he- magglutinin. PLoS One 2011;6:e29120.
Yu KL, Torri AF, Luo G, et al. Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine. Bioorg Med Chem Lett 2002;12:3379-82.
Yuan S. Drugs to cure avian influenza infection-multiple ways to prevent cell death. Cell Death Dis 2013;4:e835
Ye M, Zheng JB, Yu KJ, et al. Effects of high dose ulinastatin treatment in patients with severe pneumonia complicating in- fluenza A H1N1 infection. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2011;23:48-9.
Naganuma A, Mizuma H, Doi I, et al. A case of acute respira- tory distress syndrome induced by fulminant influenza A (H3 N2) pneumonia. Nihon Kokyuki Gakkai Zasshi 2000;38:783-7.
Munakata M, Kato R, Yokoyama H, et al. Combined therapy with hypothermia and anticytokine agents in influenza A en- cephalopathy. Brain Dev 2000;22:373-7.
Leng YX, Yang SG, Song YH, et al. Ulinastatin for acute lung injury and acute respiratory distress syndrome: A sys- tematic review and meta-analysis. World J Crit Care Med 2014;3:34-41.
Ketscher L, Hannß R, Morales DJ, et al. Selective inactiva- tion of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance. Proc Natl Acad Sci U S A 2015;112:1577-82.
Uchida Y, Watanabe C, Takemae N, et al. Identification of host genes linked with the survivability of chickens infected with recombinant viruses possessing H5N1 surface anti- gens from a highly pathogenic avian influenza virus. J Virol 2012;86:2686-95.
Liu AL, Li YF, Qi W, et al. Comparative analysis of selected innate immune-related genes following infection of immortal DF-1 cells with highly pathogenic (H5N1) and low pathogenic (H9N2) avian influenza viruses. Virus Genes 2015, in press.
Loregian A, Mercorelli B, Nannetti G, et al. Antiviral strategies against influenza virus: towards new therapeutic approaches. Cell Mol Life Sci 2014, in press.
Bauman JD, Patel D, Baker SF, et al. Crystallographic frag- ment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors. ACS Chem Biol 2013;8:2501-8.
Sheppard S. Moroxydine: the story of a mislaid antiviral. Acta Derm Venereol Suppl (Stockh) 1994;183:1-9.
Mertens T, Eggers HJ. Moroxydine. Dtsch Med Wochenschr 1980;105:184.
Dreyfus P. Treatment of influenzal infections by a moroxydine derivative. Sem Ther 1966;42:51-2.
Furuta Y, Takahashi K, Fukuda Y, et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob Agents Chemother. 2002;46:977-81.
Caroline AL, Powell DS, Bethel LM, et al. Broad spectrum antiviral activity of favipiravir (T-705): protection from high- ly lethal inhalational Rift Valley Fever. PLoS Negl Trop Dis 2014;8:e2790.
Oestereich L, Rieger T, Neumann M, et al. Evaluation of anti- viral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever. PLoS Negl Trop Dis 2014;8:e2804.
Smither SJ, Eastaugh LS, Steward JA, et al. Post-exposure efficacy of oral T-705 (Favipiravir) against inhalation- al Ebola virus infection in a mouse model. Antiviral Res 2014;104:153-5.
Safronetz D, Falzarano D, Scott DP, et al. Antiviral efficacy of favipiravir against two prominent etiological agents of han- tavirus pulmonary syndrome. Antimicrob Agents Chemother 2013;57:4673-80.
Iwai Y, Murakami K, Gomi Y, et al. Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts. PLoS One 2011;6:e19825.
Shaw ML, Klumpp K. Successes and challenges in the antiviral field. Curr Opin Virol 2013;3:483-6.
Loregian A, Coen DM. Selective anti-cytomegalovirus com- pounds discovered by screening for inhibitors of subunit inter- actions of the viral polymerase. Chem Biol 2006;13:191-200.
Fukuoka M, Minakuchi M, Kawaguchi A, et al Structure-based discovery of anti-influenza virus A compounds among medi- cines. Biochim Biophys Acta 2012;1820:90-5
Sugiyama K, Obayashi E, Kawaguchi A, et al. Structural in- sight into the essential PB1-PB2 subunit contact of the influ- enza virus RNA polymerase. EMBO J 2009;28:1803-11.
Chase G, Wunderlich K, Reuther P, et al. Identification of influ- enza virus inhibitors which disrupt of viral polymerase protein- protein interactions. Methods 2011;55:188-91.
Li C, Ba Q, Wu A, et al. A peptide derived from the C-terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly. FEBS J 2013;280:1139-49.
Nasser EH, Judd AK, Sanchez A, et al. Antiviral activity of in- fluenza virus M1 zinc finger peptides. J Virol 1996;70:8639-44.
Li L, Chang S, Xiang J, et al. Screen anti-influenza lead com- pounds that target the PA(C) subunit of H5N1 viral RNA poly- merase. PLoS One 2012;7:e35234.
Clark MP, Ledeboer MW, Davies I, et al. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J Med Chem 2014;57:6668-78.
Pagano M, Castagnolo D, Bernardini M, et al. The fight against the influenza A virus H1N1: synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors. Chem Med Chem 2014;9:129-50.
Lepri S, Nannetti G, Muratore G, et al. Optimization of small- molecule inhibitors of influenza virus polymerase: from thio- phene-3-carboxamide to polyamido scaffolds. J Med Chem 2014;57:4337-50.
Gao J, Luo X, Li Y, et al. Synthesis and biological evaluation of 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers as inhibitors of influenza A viruses. Chem Biol Drug Des 2014, in press.
Dierkes R, Warnking K, Liedmann S, et al. The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity. PLoS One 2014;9:e88520.
Elton D, Simpson-Holley M, Archer K, et al. Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway. J Virol 2001;75:408-19.
Perwitasari O, Johnson S, Yan X, et al. Verdinexor, a novel selective inhibitor of nuclear export, reduces influenza a virus replication in vitro and in vivo. J Virol 2014;88:10228-43.
Amorim MJ, Kao RY, Digard P. Nucleozin targets cytoplasmic trafficking of viral ribonucleoprotein-Rab11 complexes in influ- enza A virus infection. J Virol 2013;87:4694-703.
Su CY, Cheng TJ, Lin MI, et al. High-throughput identification of compounds targeting influenza RNA-dependent RNA poly- merase activity. Proc Natl Acad Sci USA 2010;107:19151-6.
Jiang H, Xu Y, Li L, et al. Inhibition of influenza virus replica- tion by constrained peptides targeting nucleoprotein. Antivir Chem Chemother 2011;22:119-30.
Verhelst J, Parthoens E, Schepens B, et al. Interferon-induc- ible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. J Virol 2012;86:13445-55.
Cianci C, Gerritz SW, Deminie C, et al. Influenza nucleopro- tein: promising target for antiviral chemotherapy. Antivir Chem Chemother 2012;23:77-91.
Pons M. Effect of actinomycin D on the replication of influenza virus and influenza virus RNA. Virology 1967;33:150-4.R. GASPARINI et Al.
Vogel U, Scholtissek C. Inhibition of the intracellular trans- port of influenza viral RNA by actinomycin D. Arch Virol 1995;140:1715-23.
Pons MW. The inhibition of influenza virus RNA synthesis by actinomycin D and cycloheximide. Virology 1973;51:120-8.
Lejal N, Tarus B, Bouguyon E, et al. Structure-based discovery of the novel antiviral properties of naproxen against the nu- cleoprotein of influenza A virus. Antimicrob Agents Chemother 2013;57:2231-42.
Zarubaev VV, Beliaevskaia SV, Sirotkin AK, et al. In vitro and in vivo effects of ingavirin on the ultrastructure and infectivity of influenza virus. Vopr Virusol 2011;56:21-5.
Zarubaev VV, Garshinina AV, Kalinina NA, et al. Activity of Ingavirin (6 -(1H-Imidazol-4-yl)ethylamino]-5-oxohexanoic acid) against human respiratory viruses in vivo experiments. Pharmaceuticals 2011;4:1518-1534.
Semenova NP, Prokudina EN, Livov DK, et al. Effect of the antiviral drug Ingaviruin on intracellular transformations and import into the nucleus of influenza A virus nucleocapsid pro- tein. Vopr Virusol 2010;55:17-20.
Loginova SIa, Borisevich SV, Shkliaeva OM, et al. Prophy- lactic and therapeutic efficacies of Ingavirin, a novel Rus- sian chemotherapeutic, with respect to influenza pathogen A (H5N1). Antibiot Khimioter 2010;55:10-2.
Shishkina LN, Nebol’sin VE, Skarnovich MO, et al. In vivo ef- ficacy of Ingavirin against pandemic A (H1N1/09)v influenza virus. Antibiot Khimioter 2010;55:32-5.
Kolobukhina LV, Merkulova LN, Shchelkanov MI, et al. Efficacy of ingavirin in adults with influenza. Ter Arkh 2009;81:51-4.
Galegov GA, Andronova VL, Nebol’sin VE. Antiviral effect of Ingavirin against seasonal influenza virus A/H1N1 in MDCK cell culture. Antibiot Khimioter 2009;54:19-22.
Loginova SIa, Borisevich SV, Maksimov VA, et al. Investigation of prophylactic activity of Ingavirin, a new Russian drug, against grippe A virus (H3N2). Antibiot Khimioter 2008;53:19-21.
Shul’diakov AA, Liapina EP, Kuznetsov VI. Current principles in the chemoprophylaxis of acute respiratory viral infections. Ter Arkh 2013;85:27-33.
Isaeva EI, Nebol’sin VE, Kozulina IS, et al. In vitro investiga- tion of the antiviral activity of Ingavirin against human metap- neumovirus. Vopr Virusol 2012;57:34-8.
Gubareva LV, Kaiser L, Hayden FG. Influenza virus neurami- nidase inhibitors. Lancet 2000;355:827-35.
Feng E, Ye D, Li J, et al. Recent advances in neuraminidase inhibitor development as anti-influenza drugs. ChemMedChem 2012;7:1527-36
Verma RP, Hansch C. A QSAR study on influenza neuramini- dase inhibitors. Bioorg Med Chem 2006;14:982-96.
Barroso L, Treanor J, Gubareva L, et al. Efficacy and tolerabil- ity of the oral neuraminidase inhibitor peramivir in experimen- tal human influenza: randomized, controlled trials for prophy- laxis and treatment. Antivir Ther 2005;10:901-10.
Birnkrant D, Cox E. The Emergency Use Authorization of per- amivir for treatment of 2009 H1N1 influenza. N Engl J Med 2009;361:2204-7.
Koyama K, Ogura Y, Nakai D, et al. Identification of bioac- tivating enzymes involved in the hydrolysis of laninamivir oc- tanoate, a long-acting neuraminidase inhibitor, in human pul- monary tissue. Drug Metab Dispos 2014;42:1031-8.
Weight AK, Haldar J, Alvarez de Cienfuegos L, et al. Attach- ing zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus. J Pharm Sci 2011;100:831-5.
Hayden FG, Cote KM, Douglas RG Jr. Plaque inhibition assay for drug susceptibility testing of influenza viruses. Antimicrob Agents Chemother 1980;17:865-70.
Jedrzejas MJ, Singh S, Brouillette WJ, et al. Structures of aro- matic inhibitors of influenza virus neuraminidase. Biochemistry 1995;34:3144-51.
Li Y, Silamkoti A, Kolavi G, et al. Pyrrolidinobenzoic acid in- hibitors of influenza virus neuraminidase: the hydrophobic side chain influences type A subtype selectivity. Bioorg Med Chem 2012;20:4582-9.
Kim CU, Lew W, Williams MA, et al. Structure-activity rela- tionship studies of novel carbocyclic influenza neuraminidase inhibitors. J Med Chem 1998;41:2451-60.
Kati WM, Saldivar AS, Mohamadi F, et al. GS4071 is a slow- binding inhibitor of influenza neuraminidase from both A and B strains. Biochem Biophys Res Commun 1998;244:408-13.
Kim CU, Lew W, Williams MA, et al. Influenza neuramini- dase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 1997;119:681-90.
Jang YJ, Achary R, Lee HW, et al. Synthesis and anti-influenza virus activity of 4-oxo- or thioxo-4,5-dihydrofuro,4-c]pyridin- 3(1H)-ones. Antiviral Res 2014;107:66-75.
Lou J, Yang X, Rao Z, et al. Design and synthesis of 6-oxo- 1,4,5,6-tetrahydropyrimidine-5-carboxylate derivatives as neu- raminidase inhibitors. Eur J Med Chem 2014;83:466-73.
Li J, Zhang D, Zhu X, et al. Studies on synthesis and structure- activity relationship (SAR) of derivatives of a new natural prod- uct from marine fungi as inhibitors of influenza virus neurami- nidase. Mar Drugs 2011;9:1887-901.
Ding Y, Dou J, Teng Z, et al. Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase. Arch Virol 2014;159:3269-78.
Nayak MK, Agrawal AS, Bose S, et al. Antiviral activity of bai- calin against influenza virus H1N1-pdm09 is due to modulation of NS1-mediated cellular innate immune responses. J Antimi- crob Chemother 2014;69:1298-310.
Wan Q, Wang H, Han X, et al. Baicalin inhibits TLR7/MYD88 signaling pathway activation to suppress lung inflammation in mice infected with influenza A virus. Biomed Rep 2014;2:437- 441.
Xu G, Dou J, Zhang L, et al. Inhibitory effects of baicalein on the influenza virus in vivo is determined by baicalin in the se- rum. Biol Pharm Bull 2010;33:238-43.
Nagai T, Suzuki Y, Tomimori T, et al. Antiviral activity of plant flavonoid, 5,7,4’-trihydroxy-8-methoxyflavone, from the roots of Scutellaria baicalensis against influenza A (H3N2) and B viruses. Biol Pharm Bull 1995;18:295-9.
Nagai T, Miyaichi Y, Tomimori T, et al. In vivo anti-influenza virus activity of plant flavonoids possessing inhibitory activity for influenza virus sialidase. Antiviral Res 1992;19:207-17.
Hale BG, Randall RE, Ortìn J, et al. The multifunctional NS1 protein of influenza A viruses. J Gen Virol 2008;89:2359-76.
Zhirnov OP, Konakova TE, Wolff T, et al. NS1 protein of influenza A virus down-regulates apoptosis. J Virol 2002;76:1617-25.
Kong JQ, Shen JH, Huang Y, et al. Development of a yeast two- hybrid screen for selection of A/H1N1 influenza NS1 non-struc- tural protein and human CPSF30 protein interaction inhibitors. Yao Xue Xue Bao 2010;45:388-94.
Twu KY, Noah DL, Rao P, et al. The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target. J Virol 2006;80:3957-65.
Jablonski JJ, Basu D, Engel DA, et al. Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1. Bioorg Med Chem 2012;20:487-97.
Mata MA, Satterly N, Versteeg GA, et al. Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor. Nat Chem Biol 2011;7:712-9.
Mahy BW, Cox NJ, Armstrong SJ, et al. Multiplication of influ- enza virus in the presence of cordycepin, an inhibitor of cellular RNA synthesis. Nat New Biol 1973;243:172-4.
Kurokawa M, Koyama AH, Yasuoka S, et al. Influenza virus overcomes apoptosis by rapid multiplication. Int J Mol Med 1999;3:527-30.
Zhirnov OP, Klenk HD. Control of apoptosis in influenza virus- infected cells by up-regulation of Akt and p53 signaling. Apop- tosis 2007;12:1419-32.
Palese P, Shaw ML. Orthomyxoviridae: the viruses and their replication. In: Knipe DM, Holey PM, editors. Fields Virology. 5th Edition. Vol. 2. Philadelphia: Lippincott Williams & Wilkins 2007, pp. 1647-1689.
Wurzer WJ, Planz O, Ehrhardt C, et al. Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 2003;22:2717-28.
Hinshaw VS, Olsen CW, Dybdahl-Sissoko N, et al. Apoptosis: a mechanism of cell killing by influenza A and B viruses. J Virol 1994;68:3667-73.
Jaworska J, Coulombe F, Downey J, et al. NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein. Proc Natl Acad Sci USA 2014;111:E2110-9.
Furman D, Jojic V, Kidd B, et al. Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. Mol Syst Biol 2014;10:750.
Feldman T, Kabaleeswaran V, Jang SB, et al. A class of allos- teric caspase inhibitors identified by high-throughput screen- ing. Mol Cell 2012;47:585-95.
Dai J, Wang G, Li W, et al. High-throughput screening for anti- influenza A virus drugs and study of the mechanism of procya- nidin on influenza A virus-induced autophagy. J Biomol Screen 2012;17:605-17.
Muniruzzaman S, Pan YT, Zeng Y, et al. Inhibition of glyco- protein processing by L-fructose and L-xylulose. Glycobiology 1996;6:795-803.
Hussain S, Miller JL, Harvey DJ, et al. Strain-specific antivi- ral activity of iminosugars against human influenza A viruses. J Antimicrob Chemother 2014, in press.
Oguin TH 3rd, Sharma S, Stuart AD, et al. Phospholipase D fa- cilitates efficient entry of influenza virus, allowing escape from innate immune inhibition. J Biol Chem 2014;289:25405-17.
Husain M, Cheung CY. Histone deacetylase 6 inhibits influenza A virus release by downregulating the trafficking of viral com- ponents to the plasma membrane via its substrate, acetylated microtubules. J Virol 2014;88:11229-39.
Hamamoto I, Harazaki K, Inase N, et al. Cyclosporin A inhib- its the propagation of influenza virus by interfering with a late event in the virus life cycle. Jpn J Infect Dis 2013;66:276-83.
Hsieh CF, Yen HR, Liu CH, et al. Ching-fang-pai-tu-san inhibits the release of influenza virus. J Ethnopharmacol 2012;144:533-44.
Buffinton GD, Christen S, Peterhans E, et al. Oxidative stress in lungs of mice infected with influenza A virus. Free Radic Res Commun 1992;16:99-110.
Drago L, Nicola L, Ossola F, et al. In vitro antiviral activ- ity of resveratrol against respiratory viruses. J Chemother 2008;20:393-4.
Palamara AT, Nencioni L, Aquilano K, et al. Inhibition of influenza A virus replication by resveratrol. J Infect Dis 2005;191:1719-29.
Li C, Fang JS, Lian WW, et al. In vitro antiviral effects and 3D QSAR Study of resveratrol derivatives as potent inhibi- tors of influenza H1N1 neuraminidase. Chem Biol Drug Des 2015;85:427-38.
Furuya A, Uozaki M, Yamasaki H, et al. Antiviral effects of ascorbic and dehydroascorbic acids in vitro. Int J Mol Med 2008;22:541-5.
Uozaki M, Ikeda K, Tsujimoto K, et al. Antiviral effects of de- hydroascorbic acid. Exp Ther Med 2010;1:983-986.
Khare D, Godbole NM, Pawar SD, et al. Calcitriol [1, 25[OH]2 D3] pre- and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells. Eur J Nutr 2013;52:1405-15.
Goldstein MR, Mascitelli L, Pezzetta F. Pandemic influenza A (H1N1): mandatory vitamin D supplementation? Med Hypoth- eses 2010;74:756.
Fedson DS. Pandemic influenza: a potential role for statins in treatment and prophylaxis. Clin. Infect. Dis 2006;43:199-205.
Fedson DS. Treating influenza with statins and other immu- nomodulatory agents. Antiviral Res 2013;99:417-35.
Mehrbod P, Hair-Bejo M, Tengku Ibrahim TA, et al. Simvasta- tin modulates cellular components in influenza A virus-infected cells. Int J Mol Med 2014;34:61-73.
Glück B, Schmidtke M, Walther M, et al. Simvastatin treatment showed no prophylactic effect in influenza virus-infected mice. J Med Virol 2013;85:1978-82.
Magulick JP, Frei CR, Ali SK, et al. The effect of statin therapy on the incidence of infections: a retrospective cohort analysis. Am J Med Sci 2014;347:211-6.