key: cord-0724803-oozejbs9 authors: GASPARINI, R.; AMICIZIA, D.; LAI, P.L.; BRAGAZZI, N.L.; PANATTO, D. title: Compounds with anti-influenza activity: present and future of strategies for the optimal treatment and management of influenza Part II: Future compounds against influenza virus date: 2014-12-03 journal: J Prev Med Hyg DOI: nan sha: 544a005c6288491bc6229435fddcdec62d6e24b9 doc_id: 724803 cord_uid: oozejbs9 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 mono-therapy 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. 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 dur-ing human and animal outbreaks. Indeed, during seasonal and pandemic outbreaks, antiviral drugs have usually been administered in mono-therapy 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. In the first part of this overview [1] , we described the life cycle of the influenza virus and the pharmacological action of the currently available drugs. In this second part, we will overview the molecular mechanisms and the targets of still-experimental drugs for the treatment and management of influenza. Figure 1 shows the attack points of several potential antiviral drugs. Antiviral drug research is a particularly active field and new approaches have been developed. Briefly, we can distinguish between compounds with anti-influenza activity that directly target influenza virus proteins or genes, and molecules that target host components that are essential to viral replication and propagation. Among the former group, we will focus especially on hemagglutinin (HA), Matrix protein 2 (M2) and neuraminidase (NA) inhibitors (HAIs, NAIs). The latter molecules have been implemented quite recently and may pave the way for personalized treatment and management of influenza. Moreover, it is expected that the inhibition of host factors (such as single molecules) and/or complex mechanisms (such as intracellular signaling cascades and pathways) may act against different influenza virus strains and may be less prone to the emergence of drug resistance than the inhibition of viral components [2, 3] . Therapies that combine two or more compounds belonging to the same group or different groups are also discussed. To write this overview, we mined various chemical databases, including Embase [4] , PubChem [5, 6] , Drug-Bank [7] and Chemical Abstracts Service (CAS) [8] , as well as patent repositories and clinical trials registries [9] . We also scanned extant reviews and consulted the gray literature (books, proceedings, conference abstracts, posters and congress communications) in order to increase coverage of the anti-influenza drugs included in the present article. With regard to the search strategy, we used a mining approach similar to that described in Eyer and Hruska [10] . No time or language filters were applied. To the best of our knowledge, this article constitutes the most comprehensive and up-to-date overview of antiinfluenza compounds in the literature. It can be used also as a working bibliography and a mapping review for scholars doing research in the field. Along with this paper, a database is currently being designed and developed and will be accessible at the CIRI-IT institutional website [11] . Effective antiviral compounds that interfere with the attachment and entry of the influenza virus into the host cell include triterpenoids [12] such as glycyrrhizic acid (GA) [13] , glycyrrhizin (GR) [14] , glycyrrhetinic acid [15] and further derivatives extracted from licorice and present in some Chinese medicaments. GR is the most active of these molecules and can repress the replication of H3N2 and H5N1, as well as of several viruses [16] . It can be delivered as an approved parenteral GR preparation (Stronger Neo-Minophafen C, SNMC), and glutamyl-tryptophan can be added in order to increase its activity [17, 18] . GR is able to inhibit entry of the virus into the host cell, and reduces the level of pro-inflammatory molecules such as chemokine (C-X-C motif) ligand type 10 (CXCL10), interleukin 6 (IL6), CC chemokine ligand type 2 (CCL2), and CC chemokine ligand type 5 (CCL5) [19, 20] . It also exerts an anti-apoptotic action. In addition, GR hinders monocyte recruitment and has anti-oxidant activities, inhibiting the formation of influenza virus-induced reactive oxygen species (ROS) [21] . It extensively modulates gene expression, activating interferon-gamma (IFN-gamma) and reducing the expression of Nuclear factor kappa B (NFκB), c-Jun N-terminal kinase (JNK), and p38. Furthermore, GR reduces high-mobility-group box type 1 (HMGB1) [22] . Promising glycyrrhizin derivatives include spacer-linked 1-thioglucuronide analogues [23] . GA inhibits influenza virus growth and replication in embryonated eggs [24] . Moreover, it can be used as an adjuvant in the preparation of anti-influenza vaccines [25] . Other triterpenoids [26] , such as the saponins and uralsaponins M-Y from the roots of Glycyrrhiza ura- lensis [27] , exhibit anti-influenza and anti-HIV activities. Moreover, saponins can be used as vaccine adjuvants [28] [29] [30] [31] and modulate the expression of cytokines and chemokines [32, 33] . Further triterpenoid derivatives share broad antiviral actions [34] [35] [36] [37] [38] . Dextran sulphate (DS) is a negatively charged sulphated polysaccharide. Besides inhibiting virus entry and attachment, it represses HA-dependent fusion activity [39] [40] [41] and NA-dependent activity [42] . However, mutations conferring resistance to DS are described in the literature [43] . Oxidized dextran can be administered as a prevention [44] [45] [46] . Other sulphated molecules include the sulphated syalil lipid NMS03, which is effective against IAV, Human Metapneumovirus (HMPV) and picoRNAvirus. It is assumed that it interferes with fusion, but the precise nature of its mechanism is still unknown [47] . Another potential fusion inhibitor is BTA9881, which has shown promising activity against RSV [48, 49] . Lysosomotropic agents, such as concanamycin A [50] [51] [52] [53] , the macrolide antibiotic bafilomycin A1 [54, 55] , saliphenylhalamide [56] , N,N'-Dicyclohexylcarbodiimide [52] , and chloroquine [57] [58] [59] [60] [61] [62] [63] [64] , inhibit vacuolar ATPase (V-ATPase) and reduce endosome acidification and lysosome number. They act on the CME pathway, but are unable to block clathrin caveolae-independent endocytosis. It should be stressed that the anti-influenzal activity of these compounds strongly depends on the pH of the cellular environment and that some scholars have reported conflicting findings about their in vivo effectiveness [65] . Extract from milk thistle seeds, known as silymarin, a complex mixture of flavonolignans, and its main component silibinin are active against influenza [66] . Also silybin and its derivative can block virus entry and regulate autophagy, repressing the formation of oxidative stress species and triggering activation of the extracellular signal-regulated kinase (ERK)/p38 mitogenactivated protein kinase (MAPK) and IκB kinase (IKK) cascades [67] . Other silybin derivatives include silybin fatty acid conjugates, which have strong anti-oxidant properties [68] . Compounds from Melaleuca alternifolia (tea tree) oil (TTO) concentrate (MAC) [69, 70] have a broad antimicrobial activity. In silico simulations have shown that these compounds can interfere with virus entry and fusion of the influenza virus [71, 72] . Other potential compounds include Amaryllidaceae alkaloids from Lycoris radiate, such as lycorine, hippeastrine, hemanthamine and 11-hydroxy vittatine, which can also inhibit the nuclear-to-cytoplasmic export of the ribonucleoprotein (RNP) complex [73] . Curcumin is able to inhibit virus entry and HA [74] . It also has antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial and antidiabetic properties, among others [75] . Curcumin acts against a large array of targets [76] . Curcumin is also active against other viruses [75, 77] . Rajput and collaborators showed that animals on a diet enriched in curcumin displayed an im-proved immune response [78] . Surprisingly, curcumin derivatives do not exhibit anti-influenza activity [79] . LADANIA067, extracted from the leaves of the wild blackcurrant (Ribes nigrum folium) [80, 81] , has shown antiviral activities both in vivo and in vitro, without having any effect on influenza virus metabolism or growth/ proliferation. Fattiviracin A1 is a recently discovered antiviral [82] . Besides inhibiting both IAV and IBV, it is active against HIV, HSV and VZV [83] . Lignans exert a good anti-influenza activity [84, 85] Germacrone is a molecule purified from Rhizoma curcuma. It can be effectively combined with oseltamivir [86] . Akt inhibitors are also effective entry inhibitors. These include peptide "Akt in", which may be TCL1-or TCL1b-based, MK2206 [87, 88] and Ma-xing-shi-gantang (MXSGT), a traditional Chinese herbal decoction [89] . Everolimus, an inhibitor of the PI3K-Akt-mTOR pathway, is also a valuable tool against influenza [90] . Among anti-attachment drugs, Fludase (DAS181) has potential anti-influenza virus properties [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] . This medication, which has proved capable of inhibiting human and avian influenza viruses in pre-clinical studies, acts by mimicking NA and destroying the molecules of sialic acid receptors on the host cell surface. It is also effective against NA-resistant influenza strains [92, 93, 103] . An effective class of HAIs is that of the amide derivatives [104] [105] [106] [107] . Gossypol is a natural phenolic aldehyde extracted from the cotton plant and blocks the dehydrogenase family enzymes [108, 109] . Its antiviral properties emerged during a 1970 study, in which an experimental model of influenza pneumonia was used [108] . In particular, chiral (+)-gossypol is more active than (-)-gossypol [110, 111] . Another antiviral against HA is Entry Block-peptide (EB-peptide), a peptide derived from fibroblast growth factor 4 (FGF4) [112] . EB-peptide can inhibit virus entry and attachment, being effective even when administered post-infection. Besides repressing influenza viruses, EBpeptide is also active against other viruses [113] . It can also be used as an adjuvant in the formalin-inactivated influenza whole-virus vaccine, triggering phagocytosis of influenza virions. Other peptides similar to EB-peptide are the FluPep (FP) peptides, such as FP1 (Tkip) and FP2-FP9 [114] . Tkip was designed as a mimetic of the suppressor of the cytokine signaling (SOCS) protein, which is involved in mediating the immune response to influenza. Furthermore, peptide NDFRSKT has strong antiviral properties, but with unknown therapeutic characteristics [115, 116] . Other molecules which bind to HA are collectins (CLs) [117] . Human CLs and bovine conglutinin, CL-43 and CL-46 confer protection against influenza infection [118] [119] [120] [121] [122] . A related group of molecules is the ficolins (such as H-ficolin and L-ficolin), present at high concentrations in serum and in bronchoalveolar secretions [123] . They bind not only to HA but also to NA in vitro models [124] . These proteins can be engineered in such a way as to become more active against influenza virus; for example, Chang and collaborators designed recombinant chimeric lectins consisting of mannose-binding lectin (MBL) and L-ficolin [125] . However, because of their role in the inflammatory response, their potential use in humans requires more complete analysis. Recently, agglutinins such as NICTABA, UDA [126] and protectins like protectin D1 [127] [128] [129] [130] have been found to have anti-influenza propriety [131] . An interesting compound, which binds to specific high-mannose oligosaccharides of HA is Cyanovirin-N (CVN) [132] . In 2003, O'Keefe et al. demonstrated its potent in vitro antiviral activity against a wide range of IAVs and IBVs, including NA-resistant strains, though resistance induced by mutations that affect the glycosilation site of HA seems to arise quite naturally [133] . Clarithromycin (CAM), able to inhibit influenza virus replication in vitro and in cell cultures, appears to have 3 mechanisms of action against type A seasonal Influenza virus. It was recently showed that CAM reduces the expression of human influenza virus receptors on the mucosal surface of the airways, reduces the production of nuclear factor-kB (NF-kB), and increases pH inside the endosomes [134, 135] . Norakin (Triperiden) is an anticholinergic drug that interacts with HA [136, 137] . This interaction may be indirect, being mediated by an increase in the internal pH in the pre-lysosomal compartment [138] [139] [140] . However, strains resistant to Norakin have been described [141] [142] [143] [144] . Also Norakin derivatives seem to be effective antiviral compounds [145] . Another interesting compound is nitazoxanide [146] [147] [148] [149] [150] [151] , useful for the treatment of protozoal and bacterial infections and is active against hepatitis and influenza viruses or rotaviruses. Further thiazolides act at the post-translational level by selectively blocking the maturation of viral HA at a stage preceding that of resistance to endoglycosidase H digestion, thus interfering with HA intracellular trafficking and insertion into the host plasma membrane, which is a key step in the correct assembly and exit of the virus from the host cell. Bacillus intermedius ribonuclease (BINASE) shows a good anti-influenza activity. BINASE and HA interact with sialic acid on the cell surface and penetrate into the host cell. Subsequently, viral RNA is released and cleaved by BINASE [152, 153] . High mannose-binding lectins (HMBL) are powerful influenza and HIV inhibitors [154] . Rutin, quercetin, and related compounds, extracted from elderberry fruit (Sambucus nigra L.) [155] [156] [157] [158] [159] [160] [161] are other HA inhibitors. Xylopine and rosmaricin have an amine group that interacts with HA [162, 163] . Theaflavins (TFs) from black tea have a strong anti-influenza activity, inhibiting HA and reducing the level of IL6, thus exerting an anti-inflammatory and anti-apoptotic action [164] [165] [166] . M2 inhibitors can be basically divided into 2 groups. The first includes compounds derived from the leads of amantadine and rimantadine and its hydroxylated derivatives [167] [168] [169] [170] [171] [172] . The second includes non-adamantane derivatives, which are promising drugs against influenza viruses [173] . Some of these compounds have been specifically designed for some important mutants of the M2 ion channel of IAV [174] [175] [176] [177] . Regarding molecules putatively capable of blocking the ion pump, Gasparini and coworkers recently conducted a field investigation into the effect of omeprazole family compounds (OFC) [178] on Influenza-like Illness (ILIs). The results showed that subjects treated with omeprazole family compounds displayed a lower risk of catching ILI (OR adj = 0.29, 95% CI: 0.15-0.52) than non-treated subjects. Molecular docking and molecular dynamics (MD) simulations, which are a common method of searching for new potential drugs, seem to confirm these findings [179] . The M2 Protein -Protein Data Bank (PDB) code 3C9J [180] -was simulated as being embedded in a dipalmitoylphosphatidylcholine (DPPC) membrane in complex, with its ligands amantadine and rimantadine being used as positive controls and omeprazole as a putative ligand. The thermodynamic integration method was used in order to estimate binding free energies of the ligands. Free-energy calculations imply omeprazole as a potent anti-viral drug. Also another study has suggested the antiviral properties of omeprazole against Ebolavirus [181] . Polyamines such as spermine [182, 183] , spermidine and putrescine have recently been identified as intrinsic rectifiers of potassium channels. Indeed, the M2 protein has a binding site for polyamines, which is different from the amantadine binding site [184] . Polyamines have quite recently been exploited in designing anti-influenza vaccines [185, 186] . Spiropiperidine M2 inhibitor and its derivatives appear promising in acting against amantadine-resistant viruses; in particular, spiropiperidine-9 seems to be the most active [187] . Among natural products, pinanamine derivatives [188] and 24-E-ferulate [188] have a good influenza activity. Substituted salicylanilides appear promising antiviral agents [190] [191] [192] [193] . In particular, Niclosamide [192] , which is approved for human use against helminthic infections, besides being active against influenza viruses, has also shown anti-neoplastic and broad antiviral ef-fects, being active against SARS-related coronavirus and Human Rhinovirus (HRV). Lysosomotropic agents [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] have also been already discussed. Further compounds include molecules obtained from TTO [69] [70] [71] [72] , which have already been mentioned. The cleavage of HA can be blocked not only by anti-M2 protein compounds, but also by inhibition of the necessary proteases [194] . Given the great importance of the proteases in the viral replication cycle, many authors [195, 196] have directed their research towards anti-protease medications that could block, or at least mitigate, the consequences of HA cleavage. HA can also be blocked by natural products such as Hepatocyte growth factor activator inhibitor 2 (HAI-2) [197] . Several anti-protease drugs have been studied in in vitro models, animals and humans, such as Camostat mesilate [198] , epsilon-aminocapronic acid [199] , leupeptin [200] and Aprotinin [201] , which has been approved for topical use in a small-particle aerosol formulation in Russia. A theoretical advantage of antiviral activity against enzymatic activities of the host is that these molecules would not lead to the selection of resistant viral variants. Other molecules can interfere with the mechanism of fusion of the endosomal and viral membranes [202] . Indeed, numerous small molecules that block virus infectivity by inhibiting the conformational changes required for HA-mediated membrane fusion have been identified. Russell et al. [194] have demonstrated that TBHQ (Tertbutyl-hydroquinone) stabilizes the neutral pH structure and, in this way, presumably, inhibits the conformational rearrangements required for membrane fusion. Furthermore, Leikina et al. [203] have demonstrated that human β-defensin 3, a lectin, can inhibit HA-mediated influenza viral fusion. Regarding the compounds targeted against the transcription and replication of vRNA, one of the first drugs developed is Ribavirin (RIB). RIB, also known by the trade name "Virazole", is a nucleoside analog [204] . Its mechanism of action is not completely known. However, Inosine 5'-monoposphate dehydrogenase (IMPDH) appears to be the principal target of the molecule. This inhibition diminishes the intracellular concentration of GTP (Guanosine-5'-triphosphate), and this is thought to stop viral protein synthesis and limit vRNA replication. Crotty et al. also demonstrated that RIB is a lethal vR-NA mutagen [205] . However, the need for high doses of the drug in order to have obtain good clinical results has limited the use of RIB as an anti-influenza drug, and a recent revision of the literature by Chan-Tack et al. suggests that there are no conclusive results on the beneficial use of Virazole for the treatment of influenza [206] . RIB can also be delivered as a liposome encapsulated with muramyl tripeptide (MTP-PE) [207] . α(1)-antitrypsin (AAT) [208] is a serine protease inhibitor of elastase and proteinase-3 (PR-3). This protein is produced by the liver and its expression increases particularly during the acute-phase response. It also has immunomodulatory, anti-inflammatory and tissue-protective properties, reducing influenza-related complications and morbidities. As an immunomodulator, AAT mediates the maturation and differentiation of dendritic cells (DCs) and T regulatory cells (T reg s), activating the IL1 receptor antagonist (IL1RA) and inducing IL10 release. Moreover, it exerts an anti-apoptotic effect, inhibiting caspases-1 and -3. The role of AAT in inhibiting influenza viruses is consistent with the clinical observations that subjects with AAT deficiency are exposed to the risk of severe influenza-related complications and should therefore be vaccinated [209, 210] . Stachyflin, acetylstachyflin and its phosphate esther or oxo derivatives [211, 212] exert their inhibitory activity on a variety of HA subtypes of IAV (H1, H2, H5 and H6, among others) but have no activity on H3 subtype IAV or on IBV [213] [214] [215] [216] [217] . The metabolites of stachyflin and its derivatives include compounds such as cis-fused decalin [214] . Stachyflin compounds can be delivered intranasally or orally, using PEG 400 as vehicle [211] . However, some amino acid substitutions confer resistance to stachyflin [212] . BMY-27709, a salicylamide derivative, and its analogues are other useful compounds [218, 219] . Thiobenzamide derivatives have a good activity profile. In particular, the axial disposition of the thioamide moiety has proved to be crucial to inhibitory activity [220] . Ulinastatin [221] is a protease inhibitor, which also protects lysosome integrity. Its use has been suggested for the treatment of avian influenza [221] and severe influenzarelated complications, such as encephalopathy [222] and acute respiratory distress syndrome (ARDS) [223, 224] . Indeed, a recently published meta-analysis has shown that this drug is effective in managing acute lung injury (ALI) and ARDS [225] . The ubiquitin-specific peptidase type 18 (USP18) protease inhibitor ISG15 is another promising molecule [226] . ISG15 is part of the interferon-regulated cellular cascade. USP18 was found to be one of seven genes which predict a response to influenza virus [227] . This finding was reproduced by Liu and collaborators [228] . Other antiviral strategies have been directed against the viral RNA polymerase [229, 230] . The trimeric polymerase complex has multiple enzymatic activities and can thus be targeted at different sites of action. For instance, nucleoside/nucleotide compounds have been developed against other viruses, namely HIV, HBV, etc. A historical compound is moroxydine [231] [232] [233] . It is also active against HSV and VZV. The most thoroughly studied of these molecules is Favipiravir (T-705). In vitro studies have demonstrated the high antiviral potency of the drug and mouse studies have demonstrated its protective efficacy against a wide range of influenza viruses A and B. This molecule also seems to be effective against other viruses [234] [235] [236] [237] [238] . More recently, other compounds directed towards antinucleasic activities have been studied, such as the series of hydroxypyridinone, which appears to have antiviral activity in cells [230] . On studying 33 different kinds of phytochemicals, other scholars have identified a family of drugs called marchantines, which appear to interact with the PA subunit of the endonuclease [239] . An attractive strategy for developing anti-polymerase compounds appears to be that of interfering with the subunit binding interfaces of PB1 and PA, which are very well conserved in different Influenza virus strains [240] . Thus, these compounds would reduce the transcriptional activity of the viral RNA polymerase. One such promising compound is AL18, which is also active against human cytomegalovirus [241] . Furthermore, the recent definition of the PB1/PB2 binding interface by means of crystallography [242] has prompted researchers to study synthetic peptides, such as peptide 1-37 and peptide 731-757, which seem to inhibit the interaction between PB1 and PB2 [243] [244] [245] [246] [247] . Azaindole VX-787, an inhibitor of PB2 [248] [249] [250] [251] , is able to interfere with the cap-snatching activity of the polymerase complex of the influenza virus. The small GTPase Rac1 inhibitor NSC23766 exhibits a similar activity profile [252] . Leptomycin B (LMB) inhibits nuclear export signal (NES)-mediated vRNP export, as well as NES-receptor CRM1/exportin-1 (XPO-1); however, it is somewhat toxic [253] . Verdinexor (KPT-335) [254] is a new-generation XPO-1 antagonist that is well tolerated in animal models and seems to be effective against both IAV and IBV. It is a selective inhibitor of nuclear export (SINE). Given the fundamental importance of the NP in modulating the replication cycle of the virus, many authors have investigated strategies for preventing its production. Moreover, molecules that prevent the functional polymerization of the NP monomers have also been studied, such as, for example, Nucleozin (NCZ) [255] . It also blocks viral RNA and protein synthesis and targets vRNP nuclear export and its cytoplasmatic trafficking. As a final result, fewer and smaller influenza viral particles are released. NCZ derivatives include a quite effective compound, namely 3061 (FA-2), which has been shown to inhibit the replication of the influenza A/ WSN/33 (H1N1) virus, though NP-mutant strains have displayed resistance to this drug [256] . Jiang and collaborators screened a peptide library and discovered that the NP-binding proline-rich peptide was particularly effective against influenza viruses [257] . Another interesting molecule is the interferon-inducible Mx1 protein [258, 259] . Cycloheximide (CHX), which is also active against enterovirus-71 (EV-71), coxsackievirus B, and actinomycin D, are quite effective chemicals [260] [261] [262] . Intriguingly, clinically licensed anti-cyclooxygenase-2 (COX-2) Naproxen also appears to inhibit the functional polymerization of NP monomers. Its derivatives, such as naproxen A and C0, also appear quite promising [263] . Another drug directed against the NP is Ingavirin, which has been licensed in Russia. Indeed, Ingavirin interacts with the transport of newly synthesized NPs from the cytoplasm to the nucleus [264] [265] [266] [267] [268] [269] [270] [271] [272] . It is also active against parainfluenza virus, adenoviruses and human metapneumovirus [273] . NAIs include peramivir and lanimamivir derivatives [274] [275] [276] [277] [278] [279] [280] [281] [282] [283] [284] [285] [286] [287] [288] [289] . Baicalin induces autophagy and acts against both NA [290] and NS1 [291] [292] [293] . Isoscutellarein is another compound that inhibits influenza virus sialidase. Its derivative is also active against influenza [294, 295] . Another potential strategy against influenza is to block the NS1 protein, a non-structural protein that is very important during the viral replication cycle. Indeed, the NS1 protein down-regulates the cellular production of IFN α/β. Furthermore, it has been demonstrated that NS1 also modulates other crucial aspects of influenza virus replication, namely viral RNA replication, viral protein synthesis, and general host-cell physiology [1, 296] . Finally, NS1 probably has an anti-apoptotic function in the early phases of replication. The meaning of apoptosis during influenza A virus replication is ambiguous, although it is usually considered to be a cellular antiviral defense that limits virus replication. Therefore, influenza viruses have acquired different ways of procrastinating this seeming host strategy [1] . Nonetheless, cellular pro-apoptotic factors favor the effective replication of influenza viruses, and some viral proteins, such as NA and PB1-F2, carry out pro-apoptotic tasks [1, 297] . Furthermore, some compounds that act against the NS1 protein have been studied. In this perspective, peptide-mediated inhibition of NS1 -CPSF30 has been proposed as a strategy for mitigating viral replication [298, 299] . Unfortunately, this virus-specific approach leads to viral mutation and the occurrence of drug resistance. More recently, Jablonski et al. studied a class of molecules derived from the NSC125044 compound, which displayed NS1 protein inhibition in viral replication assays [300] . Regulated in development and DNA damage responses-1 (REDD1) is a molecule that has recently emerged from comprehensive biochemical screening. Moreover, REDD1 inhibits the mTOR pathway [301] . Cordycepins extracted from Cordyceps, a genus of ascomycete fungi, are used for diverse medicinal purposes because of their different pharmacological actions with hypothetical anti-viral activity [302] . Apoptosis plays a major role in the influenza virus life cycle [303] [304] [305] [306] [307] . Indeed, in order to replicate, the virus activates the mechanism of apoptosis through the activation of caspase 3. Cellular inhibitors of apoptosis proteins (cIAPs) are essential regulators of cell death and immunity. Nucleotide-binding oligomerization domain-like receptor type 1 (NLRX1) [308] binds to viral protein PB1-F2, preventing IAV-induced macrophage apoptosis and promoting both macrophage survival and type I IFN signaling. Interestingly, compounds that inhibit this enzymatic activity could be useful as anti-influenza antivirals. Indeed, Wurzer et al. have shown that apoptotic activation by caspase 3 is required for efficient virus production [306] . Furman and collaborators have demonstrated that the apoptotic index is a predictive biomarker of influenza vaccine responsiveness [309] . However, the question of whether apoptosis is beneficial to the viral reproductive cycle or to host cells is still under debate. Moreover, Hinshaw et al. [307] demonstrated that, on inhibiting apoptosis during viral infection, influenza virus RNP complexes were retained in the nucleus. Therefore, the use of caspase 3 inhibitors could have good potential as anti-influenza drugs [310] . Autophagy (or autophagocytosis) is a catabolic mechanism that involves cellular breakdown of dysfunctional cell components through the involvement of lysosomes. Procyanidin has an anti-IAV activity [311] . L-fructose and L-xylulose can inhibit influenza virus replication [312] . Glucosidase I and glucosidase II inhibitors include iminosugars, which alter glycan processing of influenza HA and NA [313] . Raf/MEK/ERK pathway inhibitors include compounds, which act as an inhibitor of MEK1 and MEK2 [3] . NFKB inhibitors include Bortezomib [3] , among others. These proteasome inhibitors are also effective against paramyxoviruses, HRV, poliovirus, coxsackievirus, HSV and HIV. Lipid metabolism plays a fundamental role during influenza virus replication: membranes and their components, such as sphingolipids, are crucial to all steps of the viral life cycle, from attachment and membrane fusion, to intracellular transport, replication, protein sorting and budding. Infection by influenza virus stimulates phospholipase D (PLD) activity [314] . HDAC6 is an anti-IAV host factor that negatively regulates the trafficking of viral components to the host cell plasma membrane via its substrate, acetylated microtubules [315] . As an anti-influenza chemical, cyclosporin A does not act through its classical targets, namely cyclophilin A (CypA), cyclophilin B (CypB) and P-glycoprotein (Pgp) [316] , but by inhibiting influenza virus release. Ching-fang-pai-tu-san (CFPTS) has a similar action [317] . Oxidation plays a major role in influenza virus life cycle and replication [318] . With regard to anti-influenza drugs that act subsequently to the various stages of viral replication, after the formation of vRNPs, it is worth considering that Resveratrol may be useful as an antiinfluenza drug. Indeed, this compound could interfere with the translocation of RNPs from the nucleus to the cytoplasm [319] [320] [321] . Dehydroascorbic acid also has antiviral properties [322, 323] . Calcitriol prior to/or post-H1N1 exposure does not affect viral clearance but significantly reduces autophagy and restores the increased apoptosis seen on H1N1 infection to its constitutive level. However, it significantly reduces the levels of H1N1-induced TNF-α (tumor necrosis factor-alpha), RANTES, IL8, IFN-β (interferon-beta) and IFN-stimulated gene-15 (ISG15). 1,25[OH]2 D3 treatment prior to/or post-H1N1 infection significantly downregulates both IL-8 and IL-6 RNA levels [324, 325] . Publications on antiviral drugs are often devoted to the use of statins as anti-flu drugs [326] [327] [328] . In particular, Fedson has suggested treating patients affected by H5N1 with statins [326, 327] . Studies in vitro, in animals and in the field seem to support this strategy. Statins are held to act through various mechanisms: through immunomodulatory and anti-inflammatory activity, by interfering with the proteins of the cytoskeleton and the interaction between these and the lipid rafts, and by reducing the availability of intracellular cholesterol. The balanced content of cholesterol in the cell is critical to the replication of IAV. Indeed, a reduction in cholesterol could impair the infectivity of progeny influenza viruses, probably by reducing the cholesterol content of the viral envelope [328] . However, some studies have found statins to be ineffective against influenza viruses [329, 330] . Extracts from Epimedium koreanum Nakai have immunomodulatory properties [331] , also against HSV, VSV and Newcastle Disease Virus (NDV). Carrageenan [332] extracted from edible red seaweeds can be administered as a nasal spray [333] . In particular, iota-carrageenan appears to be the most effective against influenza. Cycloferon [334] [335] [336] , amixin, Larifan, Kagocel and Ragosin stimulate B cells and macrophages to produce IFN-alpha [337] . They are widely used in Russia. Apocynin, a NADPH oxidase type 2 (NOX2) inhibitor, stimulates cell superoxide production. However, in certain conditions, it can also act as a ROS production stimulator in non-phagocyte cells [338] . By contrast, NADPH oxidase type 1 (NOX1) has anti-inflammatory activity and inhibits ROS production [339, 340] . Rolipram, a selective phosphodiesterase-4 (PDE-4) inhibitor with antidepressant properties, and sertraline, a selective serotonin reuptake inhibitor (SSRI), exhibit strong antiviral activities if combined with oseltamivir [341] . The rationale for using PDE-4 is that it belongs to a family of enzymes that metabolize cyclic adenosin monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are commonly found during inflammatory and immune responses. By reducing bronchospasm and bronchoconstriction, it reduces mortality and morbidity in a mouse model. SSRI downregulates the expression of interferon-alpha, TNF-alpha, IL-6, IL-10 and T helper 1 (Th1) cells, and modulates immune responses from the Th1 toward the Th2 phenotype. Sphingosine mimetics are able to finely modulate the release of cytokines and chemokines. In one study [342] , neutralizing antibody and cytotoxic T cell responses were seen to be reduced, though still protective. As a result, the infiltration of PML and macrophages into the lung was markedly reduced, and thus also pulmonary tissue injury. DC maturation was suppressed, which limited the proliferation of specific antiviral T cells in the lung and draining lymph nodes. Furthermore, they were effective in controlling CD8(+) T cell accumulation in the lungs even when given 4 days after the onset of influenza virus infection. Leucomycin A3 (LMA3), a macrolide antibiotic, inhibits neutrophil myeloperoxidase (MPO), which contributes to the pathogenesis and progression of severe influenza-induced pneumonia, and mediates the production of hypochlorous acid, a potent tissue injury factor [343] . BG-777, derived from leukotriene B4, exerts both antiviral and stimulatory activities on the host defence system. It is also active against HIV, RSV and Coronaviruses. It recruits leukocytes and fosters the release of chemokines such as MIP1-beta and defensins [344] . QS-21 is a molecule with immunomodulatory properties, and is currently being investigated as an adjuvant for vaccines against influenza [345] . Thymalfasin (Zadaxin), which is derived from thymosin alpha-1, is another powerful adjuvant [346] [347] [348] . Canakinumab (Ilaris), an IL1-beta blocking antibody, is also a promising compound in immunotherapy [349] . Some observations should be made on influenza therapy with non-steroidal anti-inflammatory drugs. Seasonal flu is normally treated with over-the-counter (OTC) drugs, which are designed to relieve symptoms. The most common are paracetamol, acetylsalicylic acid (which, however, is contraindicated in individuals under 18 years of age) and ibuprofen or other NSAIDs. Coughing is usually mitigated by means of drugs that use dextromethorphan or acetylcistein as their active ingredient [350] [351] [352] [353] [354] [355] [356] [357] . The inflammation driven by innate immunity is usually sufficient to cure the disease. However, especially when the virus is particularly virulent or during pandemics, immunity may be dysregulated (cytokine-storm), which may give rise to very severe forms of influenza. The treatment of both seasonal and pandemic influenza therefore utilises appropriate and timely anti-inflammatory therapy. Some of the above-mentioned drugs, such as statins and naproxen, have anti-inflammatory properties; however, they are probably also able to exert a real antiviral activity. In the light of the human cases of infection by the H5N1 strain and the lethal cases caused by the H1N1pdm virus, the need for modulators of innate immunity is of particular importance. Indeed, patients with severe or fatal human infections due to the H1N1pdm virus, for instance, have high pro-inflammatory responses early in the illness. For the above-mentioned reasons, the literature often reports in vitro and animals studies which demonstrate the therapeutic utility of anti-inflammatory and immunemodulatory compounds, such as fibrates, against influenza. Gene therapy consists of modulating (up-regulating or down-regulating) genes and/or their products involved in the response to influenza [358] . microRNAs (miRNAs) are small non-coding RNA molecules (containing about 22 nucleotides) which function in RNA silencing or RNA interference (RNAi) and in the post-transcriptional regulation of gene expression. Host miRNAs are able to down-regulate the expression of viral genes. Therefore, miRNA modulation could be a promising approach in influenza treatment, despite the difficulties of delivering miRNAs to cells efficiently [359] [360] [361] [362] [363] . Small interfering RNAs (siRNAs) are also mediators of RNAi. They are short (19-26 nucleotides) and induce sequence-specific degradation of homologous mR-NA [364] [365] [366] . Long non-coding RNAs (lncRNAs) modulate various biological processes [367] . One lncRNA, in particular, plays a major role; it acts as a negative regulator of antiviral response (NRAV) and is down-regulated during influenza infection. NRAV negatively regulates the transcription of multiple critical interferon-stimulated genes (ISGs), by remodeling chromatin [368] . In the case of some compounds, the precise nature of their pharmacological activity against influenza is still unknown and requires further research. Nanoparticles are a promising nanobiotechnological tool that can act as carriers of non-conjugated nanoparticles. Silver nanoparticles [369, 370] modulate SP-A and SP-D [371] , and can be used to deliver RNAi [372] . Poly(gamma-glutamic) acid [373] , fullerenes [374] , chitosan or N-trimethyl chitosan (TMC) [375] and polymeric nanoparticles have also been investigated as vaccine adjuvants [376, 377] . However, single-walled carbon nanotubes (SWCNTs) seem to increase influenza virus pathogenicity and infectivity [378] . Combination therapies (CTs) can be divided into associations of two or more drugs directly targeting viral components, and associations of a direct-acting viral compound and a molecule targeting host components. CTs may improve clinical outcomes, reduce the risk of respiratory complications, mortality and morbidity, reduce the risks of using single drugs (such as resistance, dose-related toxicity or other side-effects) and may potentiate and enhance antiviral activity [379, 380] . CTs can, in turn, be further divided into early combination chemotherapy (ECC) and sequential multidrug chemotherapy (SMC). Furthermore, many studies have evaluated the efficacy of combining anti-inflammatory drugs with antiviral drugs in comparison with single-drug treatment. However, not all combination therapies, for instance the combination of oseltamivir with zanamivir or simvastatin with oseltamivir, are superior to monotherapy [102, 379, 380] . CTs can also exploit various chimeric monoclonal antibodies [381] . In in human studies it is important to determine the number and age of the subjects to be studied. Only if standardized methods are defined, will it be possible to correctly evaluate the antiviral potential of the compound under examination. In this perspective, it is also important to compare the antiviral activity of the hypothetical antiviral with that of reference drugs (amantadine, oseltamivir, etc) in order to ascertain the influenza antiviral index of the new molecule. In in vitro studies, it is also advisable to evaluate the capacity of the antiviral under study to induce viral resistance. In the field of medicinal chemistry, the discovery and development of a completely New Molecular Entity (NME) or compound is particularly expensive in terms of time and costs. Research could therefore be carried out along two different lines: designing/optimising new derivatives from an existing lead (such as the secondgeneration NAI laninamivir and peramivir); and repurposing/repositioning existing drugs for new potential clinical applications [382, 383] . The latter approach, also termed drug retasking or reprofiling, has already yielded promising results. While drug retargeting was initially serendipitous, it was later more systematically developed and exploited, not least by combining advanced biochemical, biophysical and bioinformatics/ cheminformatics techniques. Viroinformatics [384] and computational systems biology [385] can suggest rational inhibitors of viral transcription, replication, protein synthesis, nuclear export and assembly/release. Other strategies may emerge from gene data mining. In this regard, Bao and collaborators used a prioritizing gene approach in order to find the most important genes involved in host resistance to influenza virus [386] . They found that the response was controlled by two TNF-mediated pathways: apoptosis and TNF receptor-2 signaling pathways. In addition, systems pharmacometrics and systems pharmacology [387] could identify valuable CTs by studying drug synergy. Secondly, the available anti-influenza drugs should be used in an appropriate manner, in order to impede or to mitigate the phenomenon of viral resistance. In this regard, the first question is: what anti-inflammatory drug should be chosen? The answer should take into account the age of the patient, the toxicity and tolerability of the drug and its efficacy in alleviating the patient's symptoms. Obviously, therapy should be initiated as soon as possible, and an NSAID (aspirin only for subjects over 18 years, ibuprofen, naproxen or paracetamol [acetaminophen]) should be chosen. These compounds not only relieve the symptoms, but also equilibrate the patient's innate immunity and sometimes have a direct or indirect antiviral effect. For instance, it is interesting that reducing pro-inflammatory cytokines diminishes the activity of proteases involved in HA cleavage. In addition, the administration of acetylcysteine is useful not only be-cause of its mucolytic action, but also on account of its antioxidant activity. The choice of the antiviral should take into account the broad resistance of influenza viruses to amantadane drugs and also the fact that mono-therapy can easily lead to the emergence of novel viral resistance. In this perspective, topic drugs, such as zanamivir, have proved to generate less resistant viral strains than drugs administered orally. In addition, other antivirals, such as antiprotease drugs, could be useful in influenza therapy. These compounds could have advantages in that, being inhibitors of cellular proteins, they should be less prone to selecting resistant viral strains. However, it should be borne in mind that disturbing the cellular environment in order to disrupt viral functions could have adverse side effects. Furthermore, it has been proposed that therapeutic protocols involving a combination of two or more antivirals should be drawn up in order to reduce the development of drug-resistant viral strains and, at the same time, administer lower drug doses. Another hypothesis could be to administer two or more different antivirals alternately. Finally, the use of antivirals in the veterinary field (for example, chicken flocks) should be carefully controlled, and in this case the combined or alternated administration of at least two antiviral drugs should be the rule. It is important to realise that this implies a one world, one health, one medicine, one science approach [382, 383] , in which human and veterinary medicine cooperate in the interest of global health in an increasingly interconnected world. Compounds with antiinfluenza activity: present and future of strategies for the optimal treatment and management of influenza. Part I: influenza life-cycle and currently available drugs Emerging cellular targets for influenza antiviral agents Development of cellular signaling pathway inhibitors as new antivirals against influenza Antiviral agents targeting the influenza virus: a review and publication analysis Anti-virus research of triterpenoids in licorice Qualitative and quantitative analysis of the major constituents in chinese medical preparation Lianhua-Qingwen capsule by UPLC-DAD-QTOF-MS Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus Antiviral effects of Glycyrrhiza species The broad anti-viral agent glycyrrhizin directly modulates the fluidity of plasma membrane and HIV-1 envelope The anti-viral activity of the complex glycyrrhizic acid-alpha-glutamyl-tryptophan against experimental lethal influenza infection in white mice caused by oseltamivir-resistant strain of the virus Effect of a combination of glutamyl-tryptophan and glycyrrhizic acid on the course of acute infection caused by influenza (H3H2) virus in mice Glycyrrhizin inhibits influenza A virus uptake into the cell Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages Glycyrrhizin exerts antioxidative effects in H5N1 influenza A virus-infected cells and inhibits virus replication and pro-inflammatory gene expression HMGB1 protein binds to influenza virus nucleoprotein and promotes viral replication Synthesis and antiviral activities of spacer-linked 1-thioglucuronide analogues of glycyrrhizin Glycyrrhizic acid inhibits influenza virus growth in embryonated eggs Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spraydried and electron-beam sterilised vaccines in non-human primates Discovery of the first series of small molecule H5N1 entry inhibitors Uralsaponins M-Y, antiviral triterpenoid saponins from the roots of Glycyrrhiza uralensis Enhancement of immune responses to influenza vaccine (H3N2) by ginsenoside Re ISCOMs (immunostimulating complexes): the first decade Enhancement of the immunogenicity and protective efficacy of a mucosal influenza subunit vaccine by the saponin adjuvant GPI-0100 Influenza virosomes supplemented with GPI-0100 adjuvant: a potent vaccine formulation for antigen dose sparing Enhancement of humoral immune responses to inactivated Newcastle disease and avian influenza vaccines by oral administration of ginseng stem-and-leaf saponins in chickens Adjuvant-active fraction from Albizia julibrissin saponins improves immune responses by inducing cytokine and chemokine at the site of injection Betulin and ursolic acid synthetic derivatives as inhibitors of Papilloma virus Synthesis of triterpenoid acylates -an effective reproduction inhibitors of influenza A (H1N1) and papilloma viruses Synthesis and antiviral activity of lupane triterpenoids with modified cycle E Lupane triterpenes and derivatives with antiviral activity Functionalization, cyclization and antiviral activity of A-secotriterpenoids Dextran sulfate inhibits fusion of influenza virus and cells expressing influenza hemagglutinin with red blood cells The influence of dextran sulfate on influenza A virus fusion with erythrocyte membranes A comparative study of the effect of dextran sulfate on the fusion and the in vitro replication of influenza A and B, Semliki Forest, vesicular stomatitis, rabies, Sendai, and mumps virus Influenza virus neuraminidase contributes to the dextran sulfate-dependent suppressive replication of some influenza A virus strains Dextran sulfate-resistant A/Puerto Rico/8/34 influenza virus is associated with the emergence of specific mutations in the neuraminidase glycoprotein Experimental study of the efficiency of oxidized dextran for prevention of influenza A/H5N1 Effects of Preventive Administration of Oxidized Dextran on Liver Injury and Reparative Regeneration in Mice Infected with Influenza A/ H5N1 Virus Preventive efficacy of oxidized dextran and pathomorphological processes in mouse lungs in avian influenza A/H5N1 Highlights in the development of new antiviral agents 1,2,3,9b-Tetrahydro-5H-imidazo,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: identification of BTA9881 as a preclinical candidate Respiratory syncytial virus (RSV) prevention and treatment: past, present, and future Concanamycin A blocks influenza virus entry into cells under acidic conditions Concanamycin A: a powerful inhibitor of enveloped animal-virus entry into cells Requirement for vacuolar proton-AT-Pase activity during entry of influenza virus into cells The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections Suppression of influenza A virus replication in human lung epithelial cells by noncytotoxic concentrations bafilomycin A1 Inhibitory effect of bafilomycin A1, a specific inhibitor of vacuolar-type proton pump, on the growth of influenza A and B viruses in MDCK cells Inhibition of influenza A virus infection in vitro by saliphenylhalamide-loaded porous silicon nanoparticles Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial Use of chloroquine in viral diseases In vitro inhibition of human influenza A virus replication by chloroquine Different pH requirements are associated with divergent inhibitory effects of chloroquine on human and avian influenza A viruses Chloroquine is effective against influenza A virus in vitro but not in vivo Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model Enhancement of T cell-mediated immune responses to whole inactivated influenza virus by chloroquine treatment in vivo Chloroquine enhances replication of influenza A virus A/WSN/33 (H1N1) in dose-, time-, and MOIdependent manners in human lung epithelial cells A549 A Cutting-edge view on the current state of antiviral drug development Silibinin inhibits hepatitis C virus entry into hepatocytes by hindering clathrin-dependent trafficking Identification of 23-(s)-2-amino-3-phenylpropanoyl-silybin as an antiviral agent for influenza A virus infection in vitro and in vivo Antioxidant and antiviral activities of silybin fatty acid conjugates Activity of Melaleuca alternifolia (tea tree) oil on Influenza virus A/PR/8: study on the mechanism of action Melaleuca alternifolia concentrate inhibits in vitro entry of influenza virus into host cells Effect of tea tree (Melaleuca alternifolia) oil as a natural antimicrobial agent in lipophilic formulations Amaryllidaceae alkaloids inhibit nuclear-to-cytoplasmic export of ribonucleoprotein (RNP) complex of highly pathogenic avian influenza virus H5N1 Curcumin differs from tetrahydrocurcumin for molecular targets, signaling pathways and cellular responses Inhibition of enveloped viruses infectivity by curcumin Regulation of expression, function, and inflammatory responses of innate immune receptor Toll-like receptor-2 (TLR2) during inflammatory responses against infection Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway The effect of dietary supplementation with the natural carotenoids curcumin and lutein on broiler pigmentation and immunity Structure-activity relationship analysis of curcumin analogues on anti-influenza virus activity Antiviral activity of Ladania067, an extract from wild black currant leaves against influenza A virus in vitro and in vivo A plant extract of Ribes nigrum folium possesses anti-influenza virus activity in vitro and in vivo by preventing virus entry to host cells Fattiviracin A1, a novel antiviral agent produced by Streptomyces microflavus strain No. 2445. II. Biological properties Antiviral activity of fattiviracin FV-8 against human immunodeficiency virus type 1 (HIV-1) A new lignan glycoside and phenylethanoid glycosides from Strobilanthes cusia BREMEK Metabolites produced by actinomycetes-antiviral antibiotics and enzyme inhibitors Germacrone inhibits early stages of influenza virus infection Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro Inhibition of Akt kinase activity suppresses entryand replication of influenza virus Mechanism by which ma-xingshi-gan-tang inhibits the entry of influenza virus Inhibition of influenza A virus replication by antagonism of a PI3K-AKT-mTOR pathway member identified by gene-trap insertional mutagenesis DAS181 inhibits H5N1 influenza virus infection of human lung tissues Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein Inhibition of neuraminidase inhibitor-resistant influenza virus by DAS181, a novel sialidase fusion protein DAS181, a sialidase fusion protein, protects human airway epithelium against influenza virus infection: an in vitro pharmacodynamic analysis A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection Expanding the armamentarium against respiratory viral infections: DAS181 DAS181 and H5N1 virus infection A recombinant sialidase fusion protein effectively inhibits human parainfluenza viral infection in vitro and in vivo Inhibition of primary clinical isolates of human parainfluenza virus by DAS181 in cell culture and in a cotton rat model Sialidase fusion protein as a novel broad-spectrum inhibitor of influenza virus infection Developing new antiviral agents for influenza treatment: what does the future hold? DAS181, a novel sialidase fusion protein, protects mice from lethal avian influenza H5N1 virus infection An investigational antiviral drug, DAS181, effectively inhibits replication of zoonotic influenza A virus subtype H7N9 and protects mice from lethality Inhibition of influenza A virus (H1N1) fusion by benzenesulfonamide derivatives targeting viral hemagglutinin Strategies of development of antiviral agents directed against influenza virus replication Current status of research and development for anti-influenza virus drugs--chemotherapy for influenza Molecular mechanism underlying the action of a novel fusion inhibitor of influenza A virus Antiviral properties of gossypol in experimental influenza pneumonia Treatment of patients with influenza Synthesis and antiviral activities of novel gossypol derivatives Synthesis and anti-H5N1 activity of chiral gossypol derivatives and its analogs implicated by a viral entry blocking mechanism Inhibition of influenza virus infection by a novel antiviral peptide that targets viral attachment to cells Antiviral activity of the EB peptide against zoonotic poxviruses A novel family of peptides with potent activity against influenza A viruses Identification and characterisation of a novel anti-viral peptide against avian influenza virus H9N2 Potential of peptides as inhibitors and mimotopes: selection of carbohydrate-mimetic peptides from phage display libraries Structure and function of collectin liver 1 (CL-L1) and collectin 11 (CL-11, CL-K1) Mannose-binding lectin contributes to deleterious inflammatory response in pandemic H1N1 and avian H9N2 infection CL-43 and CL-46-three bovine collectins Anti-influenza A virus activities of mannan-binding lectins and bovine conglutinin Binding of human collectins (SP-A and MBP) to influenza virus Conglutinin acts as an opsonin for influenza A viruses Human H-ficolin inhibits replication of seasonal and pandemic influenza A viruses L-ficolin binds to the glycoproteins hemagglutinin and neuraminidase and inhibits influenza A virus infection both in vitro and in vivo Recombinant chimeric lectins consisting of mannose-binding lectin and L-ficolin are potent inhibitors of influenza A virus compared with mannose-binding lectin NICTABA and UDA, two GlcNAc-binding lectins with unique antiviral activity profiles Targeting the C-type lectins-mediated host-pathogen interactions with dextran The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza A new therapeutic strategy for lung tissue injury induced by influenza with CR2 targeting complement inhibitor Role of omega-3 PUFA-derived mediators, the protectins, in influenza virus infection Role of MBL-associated serine protease (MASP) on activation of the lectin complement pathway Treatment of influenza A (H1N1) virus infections in mice and ferrets with cyanovirin-N Potent anti-influenza activity of cyanovirin-N and interactions with viral hemagglutinin Clarithromycin inhibits progeny virus production from human influenza virus-infected host cells Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells Haemagglutinin of influenza A virus is a target for the antiviral effect of Norakin Effect of the virostatic Norakin (triperiden) on influenza virus activities Antiviral activity of Norakin (triperiden) and related anticholinergic antiparkinsonism drugs The influence of Norakin on the reproduction of influenza A and B viruses The anticholinergic anti-Parkinson drug Norakin selectively inhibits influenza virus replication Mutations in the hemagglutinin gene associated with influenza virus resistance to norakin Mapping mutations in influenza A virus resistant to norakin Relation between drug resistance and antigenicity among norakin-resistant mutants of influenza A (fowl plague) virus Factors that cause a change in the antigenic structure of of the influenza virus hemagglutinin Synthesis and anti-influenza virus activity of tricyclic compounds with a unique amine moiety A first-in-class broad-spectrum antiviral agent Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca(2+) stores Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro Analyzing the relationship of QT interval and exposure to nitazoxanide, a prospective candidate for influenza antiviral therapy -A formal TQT study Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial In vitro susceptibility of canine influenza A (H3N8) virus to nitazoxanide and tizoxanide Barnase and binase: twins with distinct fates Antiviral Activity of Binase against the Pandemic Influenza A (H1N1) Virus 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 Effects of rutin and quercetin on monooxygenase activities in experimental influenza virus infection Quercetin reduces susceptibility to influenza infection following stressful exercise Inhibitory effects of quercetin 3-rhamnoside on influenza A virus replication Effect of quercetin supplementation on lung antioxidants after experimental influenza virus infection Protective effects of quercetin during influenza virus-induced oxidative stress A nutritional supplement formula for influenza A (H5N1) infection in humans The effect of an aqueous propolis extract, of rutin and of a rutin-quercetin mixture on experimental influenza virus infection in mice Two birds with one stone? Possible dual-targeting H1N1 inhibitors from traditional Chinese medicine Screening from the world's largest TCM database against H1N1 virus Inhibition of the infectivity of influenza virus by tea polyphenols Comparison of in vitro antiviral activity of tea polyphenols against influenza A and B viruses and structure-activity relationship analysis In vitro anti-influenza virus and anti-inflammatory activities of theaflavin derivatives Amantadine, rimatadine, and related agents Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block The specific inhibition of influenza A virus maturation by amantadine: an electron microscopic examination Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008-2010 Influence of rimantadine, ribavirine and triazavirine on influenza A virus replication in human monolayer and lymphoblastoid cell lines Antiviral properties, metabolism, and pharmacokinetics of a novel azolo-1,2,4-triazinederived inhibitor of influenza A and B virus replication The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus Viral M2 ion channel protein: a promising target for anti-influenza drug discovery 3-Azatetracyclo.2.1.1(5,8).0(1,5)]undecane derivatives: from wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant Structure and inhibition of the drugresistant S31N mutant of the M2 ion channel of influenza A virus 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 Do the omeprazole family compounds exert a protective effect against influenza-like illness? Docking and molecular dynamics (MD) simulations in potential drugs discovery: an application to influenza virus M2 protein The Crystal structure of Transmembrane domain of M2 protein and Amantadine complex Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry Inactivation of influenza and Newcastle disease viruses by oxidized spermine Antiviral activity of oxidized polyamines Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein Immunogenicity, protective efficacy and mechanism of novel CCS adjuvanted influenza vaccine A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity Influence of an additional amino group on the potency of aminoadamantanes against influenza virus A. II -Synthesis of spiropiperazines and in vitro activity against influenza A H3N2 virus Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors Anti-influenza virus effect of some propolis constituents and their analogues (esters of substituted cinnamic acids) Synthesis of novel test compounds for antiviral chemotherapy of severe acute respiratory syndrome (SARS) Relevance of signaling molecules for apoptosis induction on influenza A virus replication Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects Antiviral activity of substituted salicylanilides -a review Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion Effects of protease inhibitors on replication of various myxoviruses Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection Inhibition of influenza virus infection and hemagglutinin cleavage by the protease inhibitor HAI-2 Evaluation of anti-influenza effects of camostat in mice infected with non-adapted human influenza viruses Action of epsilon-aminocaproic acid on the proteolysis system during experimental influenza in mice Inhibitory effect of a protease inhibitor, leupeptin, on the development of influenza pneumonia, mediated by concomitant bacteria Aprotinin and similar protease inhibitors as drugs against influenza Exploring the early stages of the pH-induced conformational change of influenza hemagglutinin Carbohydratebinding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins Mechanism of action of 1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (Virazole), a new broad-spectrum antiviral agent Ribavirin's antiviral mechanism of action: lethal mutagenesis? Use of ribavirin to treat influenza Therapeutic efficacy of liposome-encapsulated ribavirin and muramyl tripeptide in experimental infection with influenza or herpes simplex virus Influenza Virus H1N1 inhibition by serine protease inhibitor (serpin) antithrombin III Alpha-1 Antitrypsin Deficiency Influenza vaccination in subjects with alpha1-antitrypsin deficiency Development of anti-influenza virus drugs I: improvement of oral absorption and in vivo anti-influenza activity of Stachyflin and its derivatives Development of anti-influenza drugs: II. Improvement of oral and intranasal absorption and the anti-influenza activity of stachyflin derivatives Stachyflin and acetylstachyflin, novel anti-influenza A virus substances, produced by Stachybotrys sp. RF-7260. I. Isolation, structure elucidation and biological activities Stachyflin and acetylstachyflin, novel anti-influenza A virus substances, produced by Stachybotrys sp. RF-7260. II. Synthesis and preliminary structure-activity relationships of stachyflin derivatives Antiviral activity of stachyflin on influenza A viruses of different hemagglutinin subtypes Total synthesis of (+)-stachyflin: a potential anti-influenza A virus agent A new strategy toward the total synthesis of stachyflin, a potent anti-influenza A virus agent: concise route to the tetracyclic core structure Salicylamide inhibitors of influenza virus fusion Inhibition of influenza A virus (H1N1) fusion by benzenesulfonamide derivatives targeting viral hemagglutinin Structure-activity relationships for a series of thiobenzamide influenza fusion inhibitors derived from 1,3,3-trimethyl-5-hydroxy-cyclohexylmethylamine Drugs to cure avian influenza infection-multiple ways to prevent cell death Effects of high dose ulinastatin treatment in patients with severe pneumonia complicating influenza A H1N1 infection A case of acute respiratory distress syndrome induced by fulminant influenza A (H3 N2) pneumonia Combined therapy with hypothermia and anticytokine agents in influenza A encephalopathy Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis Selective inactivation of USP18 isopeptidase activity in vivo enhances ISG15 conjugation and viral resistance Identification of host genes linked with the survivability of chickens infected with recombinant viruses possessing H5N1 surface antigens from a highly pathogenic avian influenza virus 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 Antiviral strategies against influenza virus: towards new therapeutic approaches Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors Moroxydine: the story of a mislaid antiviral Treatment of influenzal infections by a moroxydine derivative In vitro and in vivo activities of anti-influenza virus compound T-705 Broad spectrum antiviral activity of favipiravir (T-705): protection from highly lethal inhalational Rift Valley Fever Evaluation of antiviral efficacy of ribavirin, arbidol, and T-705 (favipiravir) in a mouse model for Crimean-Congo hemorrhagic fever Post-exposure efficacy of oral T-705 (Favipiravir) against inhalational Ebola virus infection in a mouse model Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts Successes and challenges in the antiviral field Selective anti-cytomegalovirus compounds discovered by screening for inhibitors of subunit interactions of the viral polymerase Structure-based discovery of anti-influenza virus A compounds among medicines Structural insight into the essential PB1-PB2 subunit contact of the influenza virus RNA polymerase Identification of influenza virus inhibitors which disrupt of viral polymerase proteinprotein interactions A peptide derived from the C-terminus of PB1 inhibits influenza virus replication by interfering with viral polymerase assembly Antiviral activity of influenza virus M1 zinc finger peptides Screen anti-influenza lead compounds that target the PA(C) subunit of H5N1 viral RNA polymerase Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2 The fight against the influenza A virus H1N1: synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors Optimization of smallmolecule inhibitors of influenza virus polymerase: from thiophene-3-carboxamide to polyamido scaffolds Synthesis and biological evaluation of 2-oxo-pyrazine-3-carboxamide-yl nucleoside analogues and their epimers as inhibitors of influenza A viruses The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity Interaction of the influenza virus nucleoprotein with the cellular CRM1-mediated nuclear export pathway Verdinexor, a novel selective inhibitor of nuclear export, reduces influenza a virus replication in vitro and in vivo Nucleozin targets cytoplasmic trafficking of viral ribonucleoprotein-Rab11 complexes in influenza A virus infection High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity Inhibition of influenza virus replication by constrained peptides targeting nucleoprotein Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly Influenza nucleoprotein: promising target for antiviral chemotherapy Effect of actinomycin D on the replication of influenza virus and influenza virus RNA Inhibition of the intracellular transport of influenza viral RNA by actinomycin D The inhibition of influenza virus RNA synthesis by actinomycin D and cycloheximide Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus In vitro and in vivo effects of ingavirin on the ultrastructure and infectivity of influenza virus Activity of Ingavirin (6 -(1H-Imidazol-4-yl)ethylamino]-5-oxohexanoic acid) against human respiratory viruses in vivo experiments Effect of the antiviral drug Ingaviruin on intracellular transformations and import into the nucleus of influenza A virus nucleocapsid protein Prophylactic and therapeutic efficacies of Ingavirin, a novel Russian chemotherapeutic, with respect to influenza pathogen A (H5N1) In vivo efficacy of Ingavirin against pandemic A (H1N1/09)v influenza virus Efficacy of ingavirin in adults with influenza Nebol'sin VE. Antiviral effect of Ingavirin against seasonal influenza virus A/H1N1 in MDCK cell culture Investigation of prophylactic activity of Ingavirin, a new Russian drug, against grippe A virus (H3N2) Current principles in the chemoprophylaxis of acute respiratory viral infections In vitro investigation of the antiviral activity of Ingavirin against human metapneumovirus Influenza virus neuraminidase inhibitors Recent advances in neuraminidase inhibitor development as anti-influenza drugs A QSAR study on influenza neuraminidase inhibitors Efficacy and tolerability of the oral neuraminidase inhibitor peramivir in experimental human influenza: randomized, controlled trials for prophylaxis and treatment The Emergency Use Authorization of peramivir for treatment of 2009 H1N1 influenza Identification of bioactivating enzymes involved in the hydrolysis of laninamivir octanoate, a long-acting neuraminidase inhibitor, in human pulmonary tissue Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus Plaque inhibition assay for drug susceptibility testing of influenza viruses Structures of aromatic inhibitors of influenza virus neuraminidase Pyrrolidinobenzoic acid inhibitors of influenza virus neuraminidase: the hydrophobic side chain influences type A subtype selectivity Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors GS4071 is a slowbinding inhibitor of influenza neuraminidase from both A and B strains Influenza neuraminidase 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 Synthesis and anti-influenza virus activity of 4-oxo-or thioxo-4,5-dihydrofuro,4-c]pyridin-3(1H)-ones Design and synthesis of 6-oxo-1,4,5,6-tetrahydropyrimidine-5-carboxylate derivatives as neuraminidase inhibitors Studies on synthesis and structureactivity relationship (SAR) of derivatives of a new natural product from marine fungi as inhibitors of influenza virus neuraminidase Antiviral activity of baicalin against influenza A (H1N1/H3N2) virus in cell culture and in mice and its inhibition of neuraminidase Antiviral activity of baicalin against influenza virus H1N1-pdm09 is due to modulation of NS1-mediated cellular innate immune responses Baicalin inhibits TLR7/MYD88 signaling pathway activation to suppress lung inflammation in mice infected with influenza A virus Inhibitory effects of baicalein on the influenza virus in vivo is determined by baicalin in the serum Antiviral activity of plant flavonoid, 5,7,4'-trihydroxy-8-methoxyflavone, from the roots of Scutellaria baicalensis against influenza A (H3N2) and B viruses In vivo anti-influenza virus activity of plant flavonoids possessing inhibitory activity for influenza virus sialidase The multifunctional NS1 protein of influenza A viruses NS1 protein of influenza A virus down-regulates apoptosis Development of a yeast twohybrid screen for selection of A/H1N1 influenza NS1 non-structural protein and human CPSF30 protein interaction inhibitors The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target Design, synthesis, and evaluation of novel small molecule inhibitors of the influenza virus protein NS1 Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor Multiplication of influenza virus in the presence of cordycepin, an inhibitor of cellular RNA synthesis Influenza virus overcomes apoptosis by rapid multiplication Control of apoptosis in influenza virusinfected cells by up-regulation of Akt and p53 signaling Orthomyxoviridae: the viruses and their replication Caspase 3 activation is essential for efficient influenza virus propagation Apoptosis: a mechanism of cell killing by influenza A and B viruses NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein Apoptosis and other immune biomarkers predict influenza vaccine responsiveness A class of allosteric caspase inhibitors identified by high-throughput screening High-throughput screening for antiinfluenza A virus drugs and study of the mechanism of procyanidin on influenza A virus-induced autophagy Inhibition of glycoprotein processing by L-fructose and L-xylulose Strain-specific antiviral activity of iminosugars against human influenza A viruses Phospholipase D facilitates efficient entry of influenza virus, allowing escape from innate immune inhibition Histone deacetylase 6 inhibits influenza A virus release by downregulating the trafficking of viral components to the plasma membrane via its substrate, acetylated microtubules Cyclosporin A inhibits the propagation of influenza virus by interfering with a late event in the virus life cycle Ching-fang-pai-tu-san inhibits the release of influenza virus Oxidative stress in lungs of mice infected with influenza A virus In vitro antiviral activity of resveratrol against respiratory viruses Inhibition of influenza A virus replication by resveratrol In vitro antiviral effects and 3D QSAR Study of resveratrol derivatives as potent inhibitors of influenza H1N1 neuraminidase Antiviral effects of ascorbic and dehydroascorbic acids in vitro Antiviral effects of dehydroascorbic acid D3] pre-and post-treatment suppresses inflammatory response to influenza A (H1N1) infection in human lung A549 epithelial cells Pandemic influenza A (H1N1): mandatory vitamin D supplementation? Pandemic influenza: a potential role for statins in treatment and prophylaxis Treating influenza with statins and other immunomodulatory agents Simvastatin modulates cellular components in influenza A virus-infected cells Simvastatin treatment showed no prophylactic effect in influenza virus-infected mice The effect of statin therapy on the incidence of infections: a retrospective cohort analysis Epimedium koreanum Nakai displays broad spectrum of antiviral activity in vitro and in vivo by inducing cellular antiviral state Iota-carrageenan is a potent inhibitor of influenza A virus infection Carrageenan nasal spray in virus confirmed common cold: individual patient data analysis of two randomized controlled trials Cycloferon efficacy in the treatment of acute respiratory tract viral infection and influenza during the morbidity outbreak in 2009-201 The therapeutic efficacy of cycloferon and the pharmacological activity of interferon inducers Protective effect of cycloferon in experimental influenza Russian experience in screening, analysis, and clinical application of novel interferon inducers Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3 Nox1 oxidase suppresses influenza a virus-induced lung inflammation and oxidative stress NADPH oxidases as novel pharmacologic targets against influenza A virus infection Reduction of influenza virus-induced lung inflammation and mortality in animals treated with a phosophodisestrase-4 inhibitor and a selective serotonin reuptake inhibitor A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection Leucomycin A3, a 16-membered macrolide antibiotic, inhibits influenza A virus infection and disease progression Humoral and cell-mediated immune responses of humans to inactivated influenza vaccine with or without QS21 adjuvant Utility of thymosin alpha-1 (Zadaxin) as a co-adjuvant in influenza vaccines: a review Thymosin-alpha 1 (Zadaxin) enhances the immunogenicity of an adjuvated pandemic H1N1v influenza vaccine (Focetria) in hemodialyzed patients: a pilot study Augmentation of influenza antibody response in elderly men by thymosin alpha one. A double-blind placebo-controlled clinical study Influenza and meningococcal vaccinations are effective in healthy subjects treated with the interleukin-1 beta-blocking antibody canakinumab: results of an open-label, parallel group, randomized, singlecenter study Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children Influenza antiviral medications: summary for clinicians (current for the 2013-14 influenza season) Alert and Response (GAR) antiviral drugs for pandemic (H1N1) 2009: definitions and use Increased survival after gemfibrozil treatment of severe mouse influenza CCR2-antagonist prophylaxis reduces pulmonary immune pathology and markedly improves survival during influenza infection Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus Synergistic combination of N-acetylcysteine and ribavirin to protect from lethal influenza viral infection in a mouse model Combination anti-inflammatory and antiviral therapy of influenza in a cotton rat model Gene silencing: a therapeutic approach to combat influenza virus infections A computational tool for the design of live attenuated virus vaccine based on microRNA-mediated gene silencing Influenza A virus infection of human respiratory cells induces primary microRNA expression MicroRNA-based strategy to mitigate the risk of gain-of-function influenza studies A computational method for predicting regulation of human microRNAs on the influenza virus genome MicroRNA expression and virulence in pandemic influenza virus-infected mice Role and application of RNA interference in replication of influenza viruses A potential therapeutic for pandemic influenza using RNA interference Inhibition of influenza virus production in virus-infected mice by RNA interference Evidence for a crucial role of a host non-coding RNA in influenza A virus replication NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription Inhibitory effects of silver nanoparticles on H1N1 influenza A virus in vitro Inhibition of A/Human/ Hubei/3/2005 (H3N2) influenza virus infection by silver nanoparticles in vitro and in vivo Nanoparticles modulate surfactant protein A and D mediated protection against influenza A infection in vitro Lipid nanoparticles as carriers for RNAi against viral infections: current status and future perspectives Influenza hemagglutinin vaccine with poly(gamma-glutamic acid) nanoparticles enhances the protection against influenza virus infection through both humoral and cell-mediated immunity Anti-influenza activity of c60 fullerene derivatives N-trimethyl chitosan (TMC) nanoparticles loaded with influenza subunit antigen for intranasal vaccination: biological properties and immunogenicity in a mouse model Chitosan nanoparticle encapsulated hemagglutinin-split influenza virus mucosal vaccine Intranasal chitosan-DNA vaccines that protect across influenza virus subtypes Single-walled carbon nanotubes increase pandemic influenza A H1N1 virus infectivity of lung epithelial cells Therapeutics against influenza Combination chemotherapy for influenza Combination therapy using chimeric monoclonal antibodies protects mice from lethal H5N1 infection and prevents formation of escape mutants Drug repositioning: playing dirty to kill pain In vitro screening for drug repositioning Multiscale modeling of influenza A virus infection supports the development of direct-acting antivirals Identification of common biological pathways and drug targets across multiple respiratory viruses based on human host gene expression analysis Drug repurposing: a better approach for infectious disease drug discovery? Unraveling the web of viroinformatics: computational tools and databases in virus research Prioritizing genes responsible for host resistance to influenza using network approaches A critical role for immune system response in mediating anti-influenza drug synergies assessed by mechanistic modeling One world, one health, one medicine One medicine one science: a framework for exploring challenges at the intersection of animals, humans, and the environment Abbreviations AAT: alpha-1-antitrypsin; ALI: acute lung injury; ARDS: acute respiratory distress syndrome CBP: CREB binding protein; CCL: CC chemokine ligand; CCL2: CCL type2; CCL5: CCL type 5; CFPTS: Ching-fang-pai-tu-san; cGMP: cyclic guanosine monophosphate; CHX: cycloheximide; CI: confidence interval; cIAPs: cellular inhibitors of apoptosis COX: cyclooxigenase; COX-2: COX type 2; CPE: cytopathic effect; CRM: chromosomal maintenance; CRM1: CRM type 1; CTs: combination therapies; CVN: Cyanovirin-N; CXCL: chemokine (C-X-C motif) ligand; CXCL10: CXCL type 10; CypA: cyclophilin A; CypB: cyclophilin B; DC: dendritic cell; DNA: deoxyribonucleic acid; DPPC: dipalmitoylphosphatidylcholine; DS: dextran sulphate; EB-peptide: entry block peptide FGF: fibroblast growth factor; FGF4: FGF type 4; FP: FluPep; FP1: FP type 1, also known as Tkip; GA: glycyrrhizic acid; GR: glycyrrhizin; GTP: guanosine-5′-triphosphate HCV: hepatitis C virus; HGF: hepatocyte growth factor; HIV: Human Immunodeficiency Virus; HMBL: High mannose-binding lectin; HMG: 3-hydroxy-3-methylglutaryl-coenzyme A; HMGB: high-mobility-group; HMGB1: HMGB type 1; HMPV: Human Metapneumovirus; HPV: Human Papillomavirus; HRV: Human Rhinovirus; HSV: Herpes Simplex Virus; HSV-1: HSV type 1; IAV: influenza A virus; IBV: influenza B virus; IFN: interferon; IFN-α: alpha IFN; IFN-β: beta IFN; IKK: IκB kinase; IL: interleukin; IL6: IL type 6; IL8: IL type 8; IL10: IL type 10; ILI: influenza-like illness; IL1RA: IL type 1 receptor antagonist; IMPDH: Inosine 5'-monoposphate dehydrogenase; IRF: interferon-regulatory factor; IRF3: IRF type 3; ISG: interferon-stimulated gene MAPK: mitogen-activated protein kinase; MBL: mannose-binding lectin; MBP: mannose-binding protein; MD: molecular dynamics; MDCK: Madin Darby Canine Kidney cell line; MIP1-beta: macrophage inflammatory protein type 1 beta; miRNA: microRNA; MPO: myeloperoxidase; mRNA: messenger RNA; MTOC: microtubule organizing center; mTOR: mammalian target of rapamycin; MTP-PE: muramyl tripeptide -levulinyl)aminobenzyl]-5-N-acetylneuraminic acid; NFKB: nuclear factor kappa B; NOX1: NADPH oxidase type 1; NOX2: NADPH oxidase type 2; NLRX1: Nucleotide-binding oligomerization domain-like receptor type 1; NRAV: negative regulator of antiviral response OFCs: omeprazole family compounds; OR adj : adjusted odds ratio; OTC: over the counter; PA: polymerase acidic protein; PB: polymerase basic protein; PB1: PB type 1; PB1-F2: PB1 frame 2; PB2: PB type 2; PCR: polymerase chain reaction; PDB: Protein Data Bank; PDTC: pyrrolidine dithiocarbamate 3; qPCR: quantitative PCR; RE: recycling endosome; REDD1: regulated in development and DNA damage responses-1; RIB: ribavirin; RNA: ribonucleic acid; RNAi: RNA interference; RNP: ribonucleoprotein; ROS: reactive oxygen species; RSV: Respiratory Syncytial Virus; RT-PCR; SA: sialic acid; SARS: Severe Acute Respiratory Syndrome; SINE: selective inhibitor of nuclear export; siRNA: short interfering RNA; SMC: sequential multidrug chemotherapy; SOCS: Suppressor of cytokine signaling; SOCS1: SOCS type 1; SP-A: surfactant protein A; SP-D: surfactant protein D; SREBP-1: sterol regulatory element-binding protein 1