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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Insights into RNA-dependent RNA Polymerase Inhibitors as Antiinfluenza Virus Agents

Author(s): Ilaria Giacchello, Francesca Musumeci*, Ilaria D’Agostino, Chiara Greco, Giancarlo Grossi and Silvia Schenone

Volume 28 , Issue 6 , 2021

Published on: 14 January, 2020

Page: [1068 - 1090] Pages: 23

DOI: 10.2174/0929867327666200114115632

Price: $65

Abstract

Background: Influenza is a seasonal disease that affects millions of people every year and has a significant economic impact. Vaccines are the best strategy to fight this viral pathology, but they are not always available or administrable, prompting the search for antiviral drugs. RNA-dependent RNA polymerase (RdRp) recently emerged as a promising target because of its key role in viral replication and its high conservation among viral strains.

Discussion: This review presents an overview of the most interesting RdRp inhibitors that have been discussed in the literature since 2000. Compounds already approved or in clinical trials and a selection of inhibitors endowed with different scaffolds are described, along with the main features responsible for their activity.

Results: RdRp inhibitors are emerging as a new strategy to fight viral infections and the importance of this class of drugs has been confirmed by the FDA approval of baloxavir marboxil in 2018. Despite the complexity of the RdRp machine makes the identification of new compounds a challenging research topic, it is likely that in the coming years, this field will attract the interest of a number of academic and industrial scientists because of the potential strength of this therapeutic approach.

Keywords: RNA-dependent RNA polymerase inhibitors, influenza A virus, protein-protein interaction inhibitors, small molecules, antiviral drugs, PA-PB1 inhibitors.

[1]
Hause, B.M.; Collin, E.A.; Liu, R.; Huang, B.; Sheng, Z.; Lu, W.; Wang, D.; Nelson, E.A.; Li, F. Characterization of a novel influenza virus in cattle and swine: proposal for a new genus in the Orthomyxoviridae family. MBio, 2014, 5(2), e00031-e14.
[http://dx.doi.org/10.1128/mBio.00031-14] [PMID: 24595369]
[2]
Couch, R.B. Orthomyxoviruses. In Chapter 58: Medical Microbiology, 4th ed.; Baron, S., Ed.; University of Texas Medical Branch at Galveston: Galveston (TX), 1996.
[PMID: 21413353]
[3]
Joseph, U.; Su, Y.C.F.; Vijaykrishna, D.; Smith, G.J.D. The ecology and adaptive evolution of influenza A interspecies transmission. Influenza Other Respir. Viruses, 2017, 11(1), 74-84.
[http://dx.doi.org/10.1111/irv.12412] [PMID: 27426214]
[4]
Stevaert, A.; Naesens, L. The influenza virus polymerase complex: an update on its structure, functions, and significance for antiviral drug design. Med. Res. Rev., 2016, 36(6), 1127-1173.
[http://dx.doi.org/10.1002/med.21401] [PMID: 27569399]
[5]
Boktor, S.W.; Hafner, J.W. Influenza. In; StatPearls [internet], StatPearls Publishing, Treasure Island, Florida, 2021.
[PMID: 29083802]
[6]
Palese, P.; Schulman, J.L. Mapping of the influenza virus genome: identification of the hemagglutinin and the neuraminidase genes. Proc. Natl. Acad. Sci. USA, 1976, 73(6), 2142-2146.
[http://dx.doi.org/10.1073/pnas.73.6.2142] [PMID: 1064882]
[7]
Ritchey, M.B.; Palese, P.; Schulman, J.L. Mapping of the influenza virus genome. III. Identification of genes coding for nucleoprotein, membrane protein, and nonstructural protein. J. Virol., 1976, 20(1), 307-313.
[http://dx.doi.org/10.1128/JVI.20.1.307-313.1976] [PMID: 985644]
[8]
Chen, W.; Calvo, P.A.; Malide, D.; Gibbs, J.; Schubert, U.; Bacik, I.; Basta, S.; O’Neill, R.; Schickli, J.; Palese, P.; Henklein, P.; Bennink, J.R.; Yewdell, J.W. A novel influenza A virus mitochondrial protein that induces cell death. Nat. Med., 2001, 7(12), 1306-1312.
[http://dx.doi.org/10.1038/nm1201-1306] [PMID: 11726970]
[9]
Wise, H.M.; Foeglein, A.; Sun, J.; Dalton, R.M.; Patel, S.; Howard, W.; Anderson, E.C.; Barclay, W.S.; Digard, P. A complicated message: Identification of a novel PB1-related protein translated from influenza A virus segment 2 mRNA. J. Virol., 2009, 83(16), 8021-8031.
[http://dx.doi.org/10.1128/JVI.00826-09] [PMID: 19494001]
[10]
Jagger, B.W.; Wise, H.M.; Kash, J.C.; Walters, K-A.; Wills, N.M.; Xiao, Y-L.; Dunfee, R.L.; Schwartzman, L.M.; Ozinsky, A.; Bell, G.L.; Dalton, R.M.; Lo, A.; Efstathiou, S.; Atkins, J.F.; Firth, A.E.; Taubenberger, J.K.; Digard, P. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response. Science, 2012, 337(6091), 199-204.
[http://dx.doi.org/10.1126/science.1222213] [PMID: 22745253]
[11]
Wise, H.M.; Hutchinson, E.C.; Jagger, B.W.; Stuart, A.D.; Kang, Z.H.; Robb, N.; Schwartzman, L.M.; Kash, J.C.; Fodor, E.; Firth, A.E.; Gog, J.R.; Taubenberger, J.K.; Digard, P. Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain. PLoS Pathog., 2012, 8(11)e1002998
[http://dx.doi.org/10.1371/journal.ppat.1002998] [PMID: 23133386]
[12]
Selman, M.; Dankar, S.K.; Forbes, N.E.; Jia, J-J.; Brown, E.G. Adaptive mutation in influenza A virus non-structural gene is linked to host switching and induces a novel protein by alternative splicing. Emerg. Microbes Infect., 2012, 1(11)e42
[http://dx.doi.org/10.1038/emi.2012.38] [PMID: 26038410]
[13]
Muramoto, Y.; Noda, T.; Kawakami, E.; Akkina, R.; Kawaoka, Y. Identification of novel influenza A virus proteins translated from PA mRNA. J. Virol., 2013, 87(5), 2455-2462.
[http://dx.doi.org/10.1128/JVI.02656-12] [PMID: 23236060]
[14]
Yamayoshi, S.; Watanabe, M.; Goto, H.; Kawaoka, Y. Identification of a novel viral protein expressed from the PB2 segment of influenza A Virus. J. Virol., 2015, 90(1), 444-456.
[http://dx.doi.org/10.1128/JVI.02175-15] [PMID: 26491155]
[15]
Kumar, B.; Asha, K.; Khanna, M.; Ronsard, L.; Meseko, C.A.; Sanicas, M. The emerging influenza virus threat: status and new prospects for its therapy and control. Arch. Virol., 2018, 163(4), 831-844.
[http://dx.doi.org/10.1007/s00705-018-3708-y] [PMID: 29322273]
[16]
Bauman, J.D.; Patel, D.; Baker, S.F.; Vijayan, R.S.K.; Xiang, A.; Parhi, A.K.; Martínez-Sobrido, L.; LaVoie, E.J.; Das, K.; Arnold, E. Crystallographic fragment screening and structure-based optimization yields a new class of influenza endonuclease inhibitors. ACS Chem. Biol., 2013, 8(11), 2501-2508.
[http://dx.doi.org/10.1021/cb400400j] [PMID: 23978130]
[17]
Pflug, A.; Lukarska, M.; Resa-Infante, P.; Reich, S.; Cusack, S. Structural insights into RNA synthesis by the influenza virus transcription-replication machine. Virus Res., 2017, 234, 103-117.
[http://dx.doi.org/10.1016/j.virusres.2017.01.013] [PMID: 28115197]
[18]
Zhou, Z.; Liu, T.; Zhang, J.; Zhan, P.; Liu, X. Influenza A virus polymerase: an attractive target for next-generation anti-influenza therapeutics. Drug Discov. Today, 2018, 23(3), 503-518.
[http://dx.doi.org/10.1016/j.drudis.2018.01.028] [PMID: 29339107]
[19]
Jones, I.M.; Reay, P.A.; Philpott, K.L. Nuclear location of all three influenza polymerase proteins and a nuclear signal in polymerase PB2. EMBO J., 1986, 5(9), 2371-2376.
[http://dx.doi.org/10.1002/j.1460-2075.1986.tb04506.x] [PMID: 3023071]
[20]
Akkina, R.K.; Chambers, T.M.; Londo, D.R.; Nayak, D.P. Intracellular localization of the viral polymerase proteins in cells infected with influenza virus and cells expressing PB1 protein from cloned cDNA. J. Virol., 1987, 61(7), 2217-2224.
[http://dx.doi.org/10.1128/JVI.61.7.2217-2224.1987] [PMID: 2438429]
[21]
Smith, G.L.; Levin, J.Z.; Palese, P.; Moss, B. Synthesis and cellular location of the ten influenza polypeptides individually expressed by recombinant vaccinia viruses. Virology, 1987, 160(2), 336-345.
[http://dx.doi.org/10.1016/0042-6822(87)90004-3] [PMID: 3310381]
[22]
Nath, S.T.; Nayak, D.P. Function of two discrete regions is required for nuclear localization of polymerase basic protein 1 of A/WSN/33 influenza virus (H1 N1). Mol. Cell. Biol., 1990, 10(8), 4139-4145.
[http://dx.doi.org/10.1128/MCB.10.8.4139] [PMID: 2196448]
[23]
Mukaigawa, J.; Nayak, D.P. Two signals mediate nuclear localization of influenza virus (A/WSN/33) polymerase basic protein 2. J. Virol., 1991, 65(1), 245-253.
[http://dx.doi.org/10.1128/JVI.65.1.245-253.1991] [PMID: 1985200]
[24]
Nieto, A.; de la Luna, S.; Bárcena, J.; Portela, A.; Valcárcel, J.; Melero, J.A.; Ortín, J. Nuclear transport of influenza virus polymerase PA protein. Virus Res., 1992, 24(1), 65-75.
[http://dx.doi.org/10.1016/0168-1702(92)90031-4] [PMID: 1320800]
[25]
Nieto, A.; de la Luna, S.; Bárcena, J.; Portela, A.; Ortín, J. Complex structure of the nuclear translocation signal of influenza virus polymerase PA subunit. J. Gen. Virol., 1994, 75(Pt 1), 29-36.
[http://dx.doi.org/10.1099/0022-1317-75-1-29] [PMID: 8113737]
[26]
Fodor, E.; Smith, M. The PA subunit is required for efficient nuclear accumulation of the PB1 subunit of the influenza A virus RNA polymerase complex. J. Virol., 2004, 78(17), 9144-9153.
[http://dx.doi.org/10.1128/JVI.78.17.9144-9153.2004] [PMID: 15308710]
[27]
Naito, T.; Momose, F.; Kawaguchi, A.; Nagata, K. Involvement of Hsp90 in assembly and nuclear import of influenza virus RNA polymerase subunits. J. Virol., 2007, 81(3), 1339-1349.
[http://dx.doi.org/10.1128/JVI.01917-06] [PMID: 17121807]
[28]
Yamashita, M.; Krystal, M.; Palese, P. Comparison of the three large polymerase proteins of influenza A, B, and C viruses. Virology, 1989, 171(2), 458-466.
[http://dx.doi.org/10.1016/0042-6822(89)90615-6] [PMID: 2763462]
[29]
Pflug, A.; Guilligay, D.; Reich, S.; Cusack, S. Structure of influenza A polymerase bound to the viral RNA promoter. Nature, 2014, 516(7531), 355-360.
[http://dx.doi.org/10.1038/nature14008] [PMID: 25409142]
[30]
Cowling, V.H. Myc up-regulates formation of the mRNA methyl cap. Biochem. Soc. Trans., 2010, 38(6), 1598-1601.
[http://dx.doi.org/10.1042/BST0381598] [PMID: 21118133]
[31]
Dias, A.; Bouvier, D.; Crépin, T.; McCarthy, A.A.; Hart, D.J.; Baudin, F.; Cusack, S.; Ruigrok, R.W.H. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature, 2009, 458(7240), 914-918.
[http://dx.doi.org/10.1038/nature07745] [PMID: 19194459]
[32]
Pflug, A.; Gaudon, S.; Resa-Infante, P.; Lethier, M.; Reich, S.; Schulze, W.M.; Cusack, S. Capped RNA primer binding to influenza polymerase and implications for the mechanism of cap-binding inhibitors. Nucleic Acids Res., 2018, 46(2), 956-971.
[http://dx.doi.org/10.1093/nar/gkx1210] [PMID: 29202182]
[33]
Yuan, P.; Bartlam, M.; Lou, Z.; Chen, S.; Zhou, J.; He, X.; Lv, Z.; Ge, R.; Li, X.; Deng, T.; Fodor, E.; Rao, Z.; Liu, Y. Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature, 2009, 458(7240), 909-913.
[http://dx.doi.org/10.1038/nature07720] [PMID: 19194458]
[34]
DuBois, R.M.; Slavish, P.J.; Baughman, B.M.; Yun, M-K.; Bao, J.; Webby, R.J.; Webb, T.R.; White, S.W. Structural and biochemical basis for development of influenza virus inhibitors targeting the PA endonuclease. PLoS Pathog., 2012, 8(8)e1002830
[http://dx.doi.org/10.1371/journal.ppat.1002830] [PMID: 22876176]
[35]
Hara, K.; Schmidt, F.I.; Crow, M.; Brownlee, G.G. Amino acid residues in the N-terminal region of the PA subunit of influenza A virus RNA polymerase play a critical role in protein stability, endonuclease activity, cap binding, and virion RNA promoter binding. J. Virol., 2006, 80(16), 7789-7798.
[http://dx.doi.org/10.1128/JVI.00600-06] [PMID: 16873236]
[36]
Doan, L.; Handa, B.; Roberts, N.A.; Klumpp, K. Metal ion catalysis of RNA cleavage by the influenza virus endonuclease. Biochemistry, 1999, 38(17), 5612-5619.
[http://dx.doi.org/10.1021/bi9828932] [PMID: 10220350]
[37]
Steitz, T.A.; Steitz, J.A. A general two-metal-ion mechanism for catalytic RNA. Proc. Natl. Acad. Sci. USA, 1993, 90(14), 6498-6502.
[http://dx.doi.org/10.1073/pnas.90.14.6498] [PMID: 8341661]
[38]
Fedor, M.J. The role of metal ions in RNA catalysis. Curr. Opin. Struct. Biol., 2002, 12(3), 289-295.
[http://dx.doi.org/10.1016/S0959-440X(02)00324-X] [PMID: 12127446]
[39]
Palermo, G.; Cavalli, A.; Klein, M.L.; Alfonso-Prieto, M.; Dal Peraro, M.; De Vivo, M. Catalytic metal ions and enzymatic processing of DNA and RNA. Acc. Chem. Res., 2015, 48(2), 220-228.
[http://dx.doi.org/10.1021/ar500314j] [PMID: 25590654]
[40]
Poch, O.; Sauvaget, I.; Delarue, M.; Tordo, N. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J., 1989, 8(12), 3867-3874.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb08565.x] [PMID: 2555175]
[41]
Biswas, S.K.; Nayak, D.P. Mutational analysis of the conserved motifs of influenza A virus polymerase basic protein 1. J. Virol., 1994, 68(3), 1819-1826.
[http://dx.doi.org/10.1128/JVI.68.3.1819-1826.1994] [PMID: 8107244]
[42]
Tarendeau, F.; Boudet, J.; Guilligay, D.; Mas, P.J.; Bougault, C.M.; Boulo, S.; Baudin, F.; Ruigrok, R.W.H.; Daigle, N.; Ellenberg, J.; Cusack, S.; Simorre, J.P.; Hart, D.J. Structure and nuclear import function of the C-terminal domain of influenza virus polymerase PB2 subunit. Nat. Struct. Mol. Biol., 2007, 14(3), 229-233.
[http://dx.doi.org/10.1038/nsmb1212] [PMID: 17310249]
[43]
Guilligay, D.; Tarendeau, F.; Resa-Infante, P.; Coloma, R.; Crepin, T.; Sehr, P.; Lewis, J.; Ruigrok, R.W.H.; Ortin, J.; Hart, D.J.; Cusack, S. The structural basis for cap binding by influenza virus polymerase subunit PB2. Nat. Struct. Mol. Biol., 2008, 15(5), 500-506.
[http://dx.doi.org/10.1038/nsmb.1421] [PMID: 18454157]
[44]
Shinya, K.; Hamm, S.; Hatta, M.; Ito, H.; Ito, T.; Kawaoka, Y. PB2 amino acid at position 627 affects replicative efficiency, but not cell tropism, of Hong Kong H5N1 influenza A viruses in mice. Virology, 2004, 320(2), 258-266.
[http://dx.doi.org/10.1016/j.virol.2003.11.030] [PMID: 15016548]
[45]
Steel, J.; Lowen, A.C.; Mubareka, S.; Palese, P. Transmission of influenza virus in a mammalian host is increased by PB2 amino acids 627K or 627E/701N. PLoS Pathog., 2009, 5(1)e1000252
[http://dx.doi.org/10.1371/journal.ppat.1000252] [PMID: 19119420]
[46]
Aggarwal, S.; Dewhurst, S.; Takimoto, T.; Kim, B. Biochemical impact of the host adaptation-associated PB2 E627K mutation on the temperature-dependent RNA synthesis kinetics of influenza A virus polymerase complex. J. Biol. Chem., 2011, 286(40), 34504-34513.
[http://dx.doi.org/10.1074/jbc.M111.262048] [PMID: 21816827]
[47]
Ng, A.K.; Chan, W.H.; Choi, S.T.; Lam, M.K.; Lau, K.F.; Chan, P.K.; Au, S.W.; Fodor, E.; Shaw, P.C. Influenza polymerase activity correlates with the strength of interaction between nucleoprotein and PB2 through the host-specific residue K/E627. PLoS One, 2012, 7(5)e36415
[http://dx.doi.org/10.1371/journal.pone.0036415] [PMID: 22570712]
[48]
Heo, Y-A. Baloxavir: first global approval. Drugs, 2018, 78(6), 693-697.
[http://dx.doi.org/10.1007/s40265-018-0899-1] [PMID: 29623652]
[49]
Koshimichi, H.; Tsuda, Y.; Ishibashi, T.; Wajima, T. Population pharmacokinetic and exposure-response analyses of Baloxavir Marboxil in adults and adolescents including patients with influenza. J. Pharm. Sci., 2019, 108(5), 1896-1904.
[http://dx.doi.org/10.1016/j.xphs.2018.12.005] [PMID: 30557562]
[50]
Omoto, S.; Speranzini, V.; Hashimoto, T.; Noshi, T.; Yamaguchi, H.; Kawai, M.; Kawaguchi, K.; Uehara, T.; Shishido, T.; Naito, A.; Cusack, S. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci. Rep., 2018, 8(1), 9633.
[http://dx.doi.org/10.1038/s41598-018-27890-4] [PMID: 29941893]
[51]
Noshi, T.; Kitano, M.; Taniguchi, K.; Yamamoto, A.; Omoto, S.; Baba, K.; Hashimoto, T.; Ishida, K.; Kushima, Y.; Hattori, K.; Kawai, M.; Yoshida, R.; Kobayashi, M.; Yoshinaga, T.; Sato, A.; Okamatsu, M.; Sakoda, Y.; Kida, H.; Shishido, T.; Naito, A. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Antiviral Res., 2018, 160, 109-117.
[http://dx.doi.org/10.1016/j.antiviral.2018.10.008] [PMID: 30316915]
[52]
Portsmouth, S.; Kawaguchi, K.; Arai, M.; Tsuchiya, K.; Uehara, T. Cap-dependent endonuclease inhibitor s-033188 for the treatment of influenza: results from a phase 3, randomized, double-blind, placebo- and active-controlled study in otherwise healthy adolescents and adults with seasonal influenza. Open Forum Infect. Dis., 2017, 4(Suppl. 1), S734.
[http://dx.doi.org/10.1093/ofid/ofx180.001]
[53]
Hayden, F.G.; Sugaya, N.; Hirotsu, N.; Lee, N.; de Jong, M.D.; Hurt, A.C.; Ishida, T.; Sekino, H.; Yamada, K.; Portsmouth, S.; Kawaguchi, K.; Shishido, T.; Arai, M.; Tsuchiya, K.; Uehara, T.; Watanabe, A. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N. Engl. J. Med., 2018, 379(10), 913-923.
[http://dx.doi.org/10.1056/NEJMoa1716197] [PMID: 30184455]
[54]
Hirotsu, N.; Sakaguchi, H.; Sato, C.; Ishibashi, T.; Baba, K.; Omoto, S.; Shishido, T.; Tsuchiya, K.; Hayden, F.G.; Uehara, T.; Watanabe, A. Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes. Clin. Infect. Dis., 2020, 71(4), 971-981.
[http://dx.doi.org/10.1093/cid/ciz908] [PMID: 31538644]
[55]
U.S. National Library of Medicine. 9 Studies found for baloxavir marboxil. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=baloxavir+marboxil+&cntry=&state=&city=&dist=(Accessed on Feb 15, 2019)
[56]
Yogaratnam, J.; Rito, J.; Kakuda, T.N.; Fennema, H.; Gupta, K.; Jekle, C.A.; Mitchell, T.; Boyce, M.; Sahgal, O.; Balaratnam, G.; Chanda, S.; Van Remoortere, P.; Symons, J.A.; Fry, J. Antiviral activity, safety, and pharmacokinetics of AL-794, a novel oral influenza endonuclease inhibitor: results of an influenza human challenge study. J. Infect. Dis., 2019, 219(2), 177-185.
[http://dx.doi.org/10.1093/infdis/jiy410] [PMID: 30053042]
[57]
U.S. National Library of Medicine. 4 Studies found for: AL-794. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=al-794&cntry=&state=&city=&dist= (Accessed on Feb 7, 2019).
[58]
Goswami, B.B.; Borek, E.; Sharma, O.K.; Fujitaki, J.; Smith, R.A. The broad spectrum antiviral agent ribavirin inhibits capping of mRNA. Biochem. Biophys. Res. Commun., 1979, 89(3), 830-836.
[http://dx.doi.org/10.1016/0006-291X(79)91853-9] [PMID: 226095]
[59]
Vanderlinden, E.; Vrancken, B.; Van Houdt, J.; Rajwanshi, V.K.; Gillemot, S.; Andrei, G.; Lemey, P.; Naesens, L. Distinct effects of T-705 (favipiravir) and ribavirin on influenza virus replication and viral RNA synthesis. Antimicrob. Agents Chemother., 2016, 60(11), 6679-6691.
[http://dx.doi.org/10.1128/AAC.01156-16] [PMID: 27572398]
[60]
Sidwell, R.W.; Bailey, K.W.; Wong, M.H.; Barnard, D.L.; Smee, D.F. In vitro and in vivo influenza virus-inhibitory effects of viramidine. Antiviral Res., 2005, 68(1), 10-17.
[http://dx.doi.org/10.1016/j.antiviral.2005.06.003] [PMID: 16087250]
[61]
Beigel, J.H.; Bao, Y.; Beeler, J.; Manosuthi, W.; Slandzicki, A.; Dar, S.M.; Panuto, J.; Beasley, R.L.; Perez-Patrigeon, S.; Suwanpimolkul, G.; Losso, M.H.; McClure, N.; Bozzolo, D.R.; Myers, C.; Holley, H.P., Jr; Hoopes, J.; Lane, H.C.; Hughes, M.D.; Davey, R.T. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial. Lancet Infect. Dis., 2017, 17(12), 1255-1265.
[http://dx.doi.org/10.1016/S1473-3099(17)30476-0] [PMID: 28958678]
[62]
U.S. National Library of Medicine. Comparing the efficacy, safety, and tolerability of combination antivirals (amantadine, ribavirin, oseltamivir) versus oseltamivir for the treatment of influenza in adults at risk for complications. Available at: https://clinicaltrials. gov/ct2/show/NCT01227967 (Accessed on Feb 1, 2019)
[63]
Furuta, Y.; Gowen, B.B.; Takahashi, K.; Shiraki, K.; Smee, D.F.; Barnard, D.L. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res., 2013, 100(2), 446-454.
[http://dx.doi.org/10.1016/j.antiviral.2013.09.015] [PMID: 24084488]
[64]
U.S. National Library of Medicine. 44 Studies found for: favipiravir. Available at: https://clinicaltrials.gov/ct2/ results?cond= favipiravir&term=&cntry=&state=&city=&dist=(Accessed on Feb 1, 2019).
[65]
Clark, M.P.; Ledeboer, M.W.; Davies, I.; Byrn, R.A.; Jones, S.M.; Perola, E.; Tsai, A.; Jacobs, M.; Nti-Addae, K.; Bandarage, U.K.; Boyd, M.J.; Bethiel, R.S.; Court, J.J.; Deng, H.; Duffy, J.P.; Dorsch, W.A.; Farmer, L.J.; Gao, H.; Gu, W.; Jackson, K.; Jacobs, D.H.; Kennedy, J.M.; Ledford, B.; Liang, J.; Maltais, F.; Murcko, M.; Wang, T.; Wannamaker, M.W.; Bennett, H.B.; Leeman, J.R.; McNeil, C.; Taylor, W.P.; Memmott, C.; Jiang, M.; Rijnbrand, R.; Bral, C.; Germann, U.; Nezami, A.; Zhang, Y.; Salituro, F.G.; Bennani, Y.L.; Charifson, P.S. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem., 2014, 57(15), 6668-6678.
[http://dx.doi.org/10.1021/jm5007275] [PMID: 25019388]
[66]
Tsai, A.W.; McNeil, C.F.; Leeman, J.R.; Bennett, H.B.; Nti-Addae, K.; Huang, C.; Germann, U.A.; Byrn, R.A.; Berlioz-Seux, F.; Rijnbrand, R.; Clark, M.P.; Charifson, P.S.; Jones, S.M. Novel ranking system for identifying efficacious anti-influenza virus PB2 inhibitors. Antimicrob. Agents Chemother., 2015, 59(10), 6007-6016.
[http://dx.doi.org/10.1128/AAC.00781-15] [PMID: 26169418]
[67]
Fu, Y.; Gaelings, L.; Söderholm, S.; Belanov, S.; Nandania, J.; Nyman, T.A.; Matikainen, S.; Anders, S.; Velagapudi, V.; Kainov, D.E. JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses. Antiviral Res., 2016, 133, 23-31.
[http://dx.doi.org/10.1016/j.antiviral.2016.07.008] [PMID: 27451344]
[68]
U.S. National Library of Medicine. 4 Studies found for: VX-787. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=vx-787&cntry=&state=&city=&dist= Accessed on Feb 1, 2019).
[69]
Byrn, R.A.; Jones, S.M.; Bennett, H.B.; Bral, C.; Clark, M.P.; Jacobs, M.D.; Kwong, A.D.; Ledeboer, M.W.; Leeman, J.R.; McNeil, C.F.; Murcko, M.A.; Nezami, A.; Perola, E.; Rijnbrand, R.; Saxena, K.; Tsai, A.W.; Zhou, Y.; Charifson, P.S. Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob. Agents Chemother., 2015, 59(3), 1569-1582.
[http://dx.doi.org/10.1128/AAC.04623-14] [PMID: 25547360]
[70]
Naesens, L.; Stevaert, A.; Vanderlinden, E. Antiviral therapies on the horizon for influenza. Curr. Opin. Pharmacol., 2016, 30, 106-115.
[http://dx.doi.org/10.1016/j.coph.2016.08.003] [PMID: 27570127]
[71]
Iwai, Y.; Murakami, K.; Gomi, Y.; Hashimoto, T.; Asakawa, Y.; Okuno, Y.; Ishikawa, T.; Hatakeyama, D.; Echigo, N.; Kuzuhara, T. Anti-influenza activity of marchantins, macrocyclic bisbibenzyls contained in liverworts. PLoS One, 2011, 6(5)e19825
[http://dx.doi.org/10.1371/journal.pone.0019825] [PMID: 21625478]
[72]
Nakayama, M.; Suzuki, K.; Toda, M.; Okubo, S.; Hara, Y.; Shimamura, T. Inhibition of the infectivity of influenza virus by tea polyphenols. Antiviral Res., 1993, 21(4), 289-299.
[http://dx.doi.org/10.1016/0166-3542(93)90008-7] [PMID: 8215301]
[73]
Imanishi, N.; Tuji, Y.; Katada, Y.; Maruhashi, M.; Konosu, S.; Mantani, N.; Terasawa, K.; Ochiai, H. Additional inhibitory effect of tea extract on the growth of influenza A and B viruses in MDCK cells. Microbiol. Immunol., 2002, 46(7), 491-494.
[http://dx.doi.org/10.1111/j.1348-0421.2002.tb02724.x] [PMID: 12222936]
[74]
Song, J.M.; Lee, K.H.; Seong, B.L. Antiviral effect of catechins in green tea on influenza virus. Antiviral Res., 2005, 68(2), 66-74.
[http://dx.doi.org/10.1016/j.antiviral.2005.06.010] [PMID: 16137775]
[75]
Ling, J.X.; Wei, F.; Li, N.; Li, J.L.; Chen, L.J.; Liu, Y.Y.; Luo, F.; Xiong, H.R.; Hou, W.; Yang, Z.Q. Amelioration of influenza virus-induced reactive oxygen species formation by epigallocatechin gallate derived from green tea. Acta Pharmacol. Sin., 2012, 33(12), 1533-1541.
[http://dx.doi.org/10.1038/aps.2012.80] [PMID: 22941291]
[76]
Kuzuhara, T.; Iwai, Y.; Takahashi, H.; Hatakeyama, D.; Echigo, N. Green tea catechins inhibit the endonuclease activity of influenza A virus RNA polymerase. PLoS Curr., 2009, 1RRN1052
[http://dx.doi.org/10.1371/currents.rrn1052]] [PMID: 20025206]
[77]
Kowalinski, E.; Zubieta, C.; Wolkerstorfer, A.; Szolar, O.H.J.; Ruigrok, R.W.H.; Cusack, S. Structural analysis of specific metal chelating inhibitor binding to the endonuclease domain of influenza pH1N1 (2009) polymerase. PLoS Pathog., 2012, 8(8)e1002831
[http://dx.doi.org/10.1371/journal.ppat.1002831] [PMID: 22876177]
[78]
Chen, E.; Swift, R.V.; Alderson, N.; Feher, V.A.; Feng, G-S.; Amaro, R.E. Computation-guided discovery of influenza endonuclease inhibitors. ACS Med. Chem. Lett., 2014, 5(1), 61-64.
[http://dx.doi.org/10.1021/ml4003474] [PMID: 24490002]
[79]
Fudo, S.; Yamamoto, N.; Nukaga, M.; Odagiri, T.; Tashiro, M.; Neya, S.; Hoshino, T. Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase. Bioorg. Med. Chem., 2015, 23(17), 5466-5475.
[http://dx.doi.org/10.1016/j.bmc.2015.07.046] [PMID: 26252962]
[80]
Carcelli, M.; Rogolino, D.; Bacchi, A.; Rispoli, G.; Fisicaro, E.; Compari, C.; Sechi, M.; Stevaert, A.; Naesens, L. Metal-chelating 2-hydroxyphenyl amide pharmacophore for inhibition of influenza virus endonuclease. Mol. Pharm., 2014, 11(1), 304-316.
[http://dx.doi.org/10.1021/mp400482a] [PMID: 24206028]
[81]
Rogolino, D.; Bacchi, A.; De Luca, L.; Rispoli, G.; Sechi, M.; Stevaert, A.; Naesens, L.; Carcelli, M. Investigation of the salicylaldehyde thiosemicarbazone scaffold for inhibition of influenza virus PA endonuclease. J. Biol. Inorg. Chem., 2015, 20(7), 1109-1121.
[http://dx.doi.org/10.1007/s00775-015-1292-0] [PMID: 26323352]
[82]
Pala, N.; Stevaert, A.; Dallocchio, R.; Dessì, A.; Rogolino, D.; Carcelli, M.; Sanna, V.; Sechi, M.; Naesens, L. Virtual screening and biological validation of novel influenza virus PA endonuclease inhibitors. ACS Med. Chem. Lett., 2015, 6(8), 866-871.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00109] [PMID: 26288686]
[83]
Parkes, K.E.; Ermert, P.; Fässler, J.; Ives, J.; Martin, J.A.; Merrett, J.H.; Obrecht, D.; Williams, G.; Klumpp, K. Use of a pharmacophore model to discover a new class of influenza endonuclease inhibitors. J. Med. Chem., 2003, 46(7), 1153-1164.
[http://dx.doi.org/10.1021/jm020334u] [PMID: 12646026]
[84]
Yuan, S.; Chu, H.; Singh, K.; Zhao, H.; Zhang, K.; Kao, R.Y.; Chow, B.K.C.; Zhou, J.; Zheng, B-J. A novel small-molecule inhibitor of influenza A virus acts by suppressing PA endonuclease activity of the viral polymerase. Sci. Rep., 2016, 6, 22880.
[http://dx.doi.org/10.1038/srep22880] [PMID: 26956222]
[85]
Parhi, A.K.; Xiang, A.; Bauman, J.D.; Patel, D.; Vijayan, R.S.; Das, K.; Arnold, E.; Lavoie, E.J. Phenyl substituted 3-hydroxypyridin-2(1H)-ones: inhibitors of influenza A endonuclease. Bioorg. Med. Chem., 2013, 21(21), 6435-6446.
[http://dx.doi.org/10.1016/j.bmc.2013.08.053] [PMID: 24055080]
[86]
Credille, C.V.; Chen, Y.; Cohen, S.M. Fragment-based identification of influenza endonuclease inhibitors. J. Med. Chem., 2016, 59(13), 6444-6454.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00628] [PMID: 27291165]
[87]
Vedula, M.S.; Jennepalli, S.; Aryasomayajula, R.; Rondla, S.R.; Musku, M.R.; Kura, R.R.; Bandi, P.R. Novel nucleosides as potent influenza viral inhibitors. Bioorg. Med. Chem., 2010, 18(17), 6329-6339.
[http://dx.doi.org/10.1016/j.bmc.2010.07.017] [PMID: 20674371]
[88]
Abdel-Magid, A.F. Influenza RNA-dependent RNA polymerase (RdRp) Inhibitors: potential new therapy for influenza treatment. ACS Med. Chem. Lett., 2013, 4(12), 1133-1134.
[http://dx.doi.org/10.1021/ml400411e] [PMID: 24900618]
[89]
Lin, C.; Sun, C.; Liu, X.; Zhou, Y.; Hussain, M.; Wan, J.; Li, M.; Li, X.; Jin, R.; Tu, Z.; Zhang, J. Design, synthesis, and in vitro biological evaluation of novel 6-methyl-7-substituted-7-deaza purine nucleoside analogs as anti-influenza A agents. Antiviral Res., 2016, 129, 13-20.
[http://dx.doi.org/10.1016/j.antiviral.2016.01.005] [PMID: 26802557]
[90]
Kumaki, Y.; Day, C.W.; Smee, D.F.; Morrey, J.D.; Barnard, D.L. In vitro and in vivo efficacy of fluorodeoxycytidine analogs against highly pathogenic avian influenza H5N1, seasonal, and pandemic H1N1 virus infections. Antiviral Res., 2011, 92(2), 329-340.
[http://dx.doi.org/10.1016/j.antiviral.2011.09.001] [PMID: 21925541]
[91]
Su, C.Y.; Cheng, T.J.R.; Lin, M.I.; Wang, S.Y.; Huang, W.I.; Lin-Chu, S.Y.; Chen, Y.H.; Wu, C.Y.; Lai, M.M.C.; Cheng, W.C.; Wu, Y.T.; Tsai, M.D.; Cheng, Y.S.; Wong, C.H. High-throughput identification of compounds targeting influenza RNA-dependent RNA polymerase activity. Proc. Natl. Acad. Sci. USA, 2010, 107(45), 19151-19156.
[http://dx.doi.org/10.1073/pnas.1013592107] [PMID: 20974907]
[92]
Ortigoza, M.B.; Dibben, O.; Maamary, J.; Martinez-Gil, L.; Leyva-Grado, V.H.; Abreu, P., Jr; Ayllon, J.; Palese, P.; Shaw, M.L. A novel small molecule inhibitor of influenza A viruses that targets polymerase function and indirectly induces interferon. PLoS Pathog., 2012, 8(4)e1002668
[http://dx.doi.org/10.1371/journal.ppat.1002668] [PMID: 22577360]
[93]
Roch, F.F.; Hinterkörner, G.; Menke, J.; Tang, G.Q.; Cusack, S.; Butzendobler, B.; Buschmann, H.; Datta, K.; Wolkerstorfer, A. An RNA hybridization assay for screening influenza A virus polymerase inhibitors using the entire ribonucleoprotein complex. Assay Drug Dev. Technol., 2015, 13(8), 488-506.
[http://dx.doi.org/10.1089/adt.2015.668] [PMID: 26461433]
[94]
Liu, T.; Liu, M.; Chen, F.; Chen, F.; Tian, Y.; Huang, Q.; Liu, S.; Yang, J. A small-molecule compound has anti-influenza A virus activity by acting as a “PB2 inhibitor”. Mol. Pharm., 2018, 15(9), 4110-4120.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00531] [PMID: 30102858]
[95]
Massari, S.; Goracci, L.; Desantis, J.; Tabarrini, O. Polymerase acidic protein-basic protein 1 (PA-PB1) protein-protein interaction as a target for next-generation anti-influenza therapeutics. J. Med. Chem., 2016, 59(17), 7699-7718.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01474] [PMID: 27046062]
[96]
D’Agostino, I.; Giacchello, I.; Nannetti, G.; Fallacara, A.L.; Deodato, D.; Musumeci, F.; Grossi, G.; Palù, G.; Cau, Y.; Trist, I.M.; Loregian, A.; Schenone, S.; Botta, M. Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction. Eur. J. Med. Chem., 2018, 157, 743-758.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.032] [PMID: 30142611]
[97]
He, X.; Zhou, J.; Bartlam, M.; Zhang, R.; Ma, J.; Lou, Z.; Li, X.; Li, J.; Joachimiak, A.; Zeng, Z.; Ge, R.; Rao, Z.; Liu, Y. Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus. Nature, 2008, 454(7208), 1123-1126.
[http://dx.doi.org/10.1038/nature07120] [PMID: 18615018]
[98]
Obayashi, E.; Yoshida, H.; Kawai, F.; Shibayama, N.; Kawaguchi, A.; Nagata, K.; Tame, J.R.H.; Park, S-Y. The structural basis for an essential subunit interaction in influenza virus RNA polymerase. Nature, 2008, 454(7208), 1127-1131.
[http://dx.doi.org/10.1038/nature07225] [PMID: 18660801]
[99]
Moen, S.O.; Abendroth, J.; Fairman, J.W.; Baydo, R.O.; Bullen, J.; Kirkwood, J.L.; Barnes, S.R.; Raymond, A.C.; Begley, D.W.; Henkel, G.; McCormack, K.; Tam, V.C.; Phan, I.; Staker, B.L.; Stacy, R.; Myler, P.J.; Lorimer, D.; Edwards, T.E. Structural analysis of H1N1 and H7N9 influenza A virus PA in the absence of PB1. Sci. Rep., 2014, 4, 5944.
[http://dx.doi.org/10.1038/srep05944] [PMID: 25089892]
[100]
Liu, H.; Yao, X. Molecular basis of the interaction for an essential subunit PA-PB1 in influenza virus RNA polymerase: insights from molecular dynamics simulation and free energy calculation. Mol. Pharm., 2010, 7(1), 75-85.
[http://dx.doi.org/10.1021/mp900131p] [PMID: 19883112]
[101]
Ghanem, A.; Mayer, D.; Chase, G.; Tegge, W.; Frank, R.; Kochs, G.; García-Sastre, A.; Schwemmle, M. Peptide-mediated interference with influenza A virus polymerase. J. Virol., 2007, 81(14), 7801-7804.
[http://dx.doi.org/10.1128/JVI.00724-07] [PMID: 17494067]
[102]
Fukuoka, M.; Minakuchi, M.; Kawaguchi, A.; Nagata, K.; Kamatari, Y.O.; Kuwata, K. Structure-based discovery of anti-influenza virus A compounds among medicines. Biochim. Biophys. Acta, 2012, 1820(2), 90-95.
[http://dx.doi.org/10.1016/j.bbagen.2011.11.003] [PMID: 22108550]
[103]
Muratore, G.; Mercorelli, B.; Goracci, L.; Cruciani, G.; Digard, P.; Palù, G.; Loregian, A. Human cytomegalovirus inhibitor AL18 also possesses activity against influenza A and B viruses. Antimicrob. Agents Chemother., 2012, 56(11), 6009-6013.
[http://dx.doi.org/10.1128/AAC.01219-12] [PMID: 22908168]
[104]
Muratore, G.; Goracci, L.; Mercorelli, B.; Foeglein, Á.; Digard, P.; Cruciani, G.; Palù, G.; Loregian, A. Small molecule inhibitors of influenza A and B viruses that act by disrupting subunit interactions of the viral polymerase. Proc. Natl. Acad. Sci. USA, 2012, 109(16), 6247-6252.
[http://dx.doi.org/10.1073/pnas.1119817109] [PMID: 22474359]
[105]
Massari, S.; Nannetti, G.; Desantis, J.; Muratore, G.; Sabatini, S.; Manfroni, G.; Mercorelli, B.; Cecchetti, V.; Palù, G.; Cruciani, G.; Loregian, A.; Goracci, L.; Tabarrini, O. A broad anti-influenza hybrid small molecule that potently disrupts the interaction of polymerase acidic protein-basic protein 1 (PA-PB1) subunits. J. Med. Chem., 2015, 58(9), 3830-3842.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00012] [PMID: 25856229]
[106]
Yuan, S.; Chu, H.; Zhao, H.; Zhang, K.; Singh, K.; Chow, B.K.C.; Kao, R.Y.T.; Zhou, J.; Zheng, B.J. Identification of a small-molecule inhibitor of influenza virus via disrupting the subunits interaction of the viral polymerase. Antiviral Res., 2016, 125, 34-42.
[http://dx.doi.org/10.1016/j.antiviral.2015.11.005] [PMID: 26593979]
[107]
Takizawa, N.; Kimura, T.; Watanabe, T.; Shibasaki, M. Anti-influenza virus activity of a salcomine derivative mediated by inhibition of viral RNA synthesis. Arch. Virol., 2018, 163(6), 1607-1614.
[http://dx.doi.org/10.1007/s00705-018-3779-9] [PMID: 29497849]
[108]
Kessler, U.; Castagnolo, D.; Pagano, M.; Deodato, D.; Bernardini, M.; Pilger, B.; Ranadheera, C.; Botta, M. Discovery and synthesis of novel benzofurazan derivatives as inhibitors of influenza A virus. Bioorg. Med. Chem. Lett., 2013, 23(20), 5575-5577.
[http://dx.doi.org/10.1016/j.bmcl.2013.08.048] [PMID: 24012120]
[109]
Pagano, M.; Castagnolo, D.; Bernardini, M.; Fallacara, A.L.; Laurenzana, I.; Deodato, D.; Kessler, U.; Pilger, B.; Stergiou, L.; Strunze, S.; Tintori, C.; Botta, M. The fight against the influenza A virus H1N1: synthesis, molecular modeling, and biological evaluation of benzofurazan derivatives as viral RNA polymerase inhibitors. ChemMedChem, 2014, 9(1), 129-150.
[http://dx.doi.org/10.1002/cmdc.201300378] [PMID: 24285596]
[110]
Tintori, C.; Laurenzana, I.; Fallacara, A.L.; Kessler, U.; Pilger, B.; Stergiou, L.; Botta, M. High-throughput docking for the identification of new influenza A virus polymerase inhibitors targeting the PA-PB1 protein-protein interaction. Bioorg. Med. Chem. Lett., 2014, 24(1), 280-282.
[http://dx.doi.org/10.1016/j.bmcl.2013.11.019] [PMID: 24314669]
[111]
Trist, I.M.L.; Nannetti, G.; Tintori, C.; Fallacara, A.L.; Deodato, D.; Mercorelli, B.; Palù, G.; Wijtmans, M.; Gospodova, T.; Edink, E.; Verheij, M.; de Esch, I.; Viteva, L.; Loregian, A.; Botta, M. 4,6-Diphenylpyridines as promising novel anti-influenza agents targeting the PA-PB1 protein-protein interaction: structure-activity relationships exploration with the aid of molecular modeling. J. Med. Chem., 2016, 59(6), 2688-2703.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01935] [PMID: 26924568]
[112]
World Heath Organization. Regional Office for Europe. Pandemic influenza, Available at: http://www.euro.who. int/en/health-topics/communicable-diseases/influenza/pandemic-influenza (Accessed on Feb 13, 2019).
[113]
Reich, S.; Guilligay, D.; Pflug, A.; Malet, H.; Berger, I.; Crépin, T.; Hart, D.; Lunardi, T.; Nanao, M.; Ruigrok, R.W.H.; Cusack, S. Structural insight into Cap-snatching and RNA synthesis by influenza polymerase. Nature, 2014, 516(7531), 361-366.
[http://dx.doi.org/10.1038/nature14009] [PMID: 25409151]
[114]
RCSB Protein Data Bank. https://www.rcsb.org/structure/ 4WSB (Accessed on Nov 17, 2020)
[115]
Schrödinger Pymol:. https://pymol.org/2/ (Accessed on Nov 17, 2020).
[116]
RCSB Protein Data Bank. https://www.rcsb.org/structure/ 6FS6 (Accessed on Nov 17, 2020)
[117]
Rose, A.S.; Bradley, A.R.; Valasatava, Y.; Duarte, J.M.; Prlic, A.; Rose, P.W. NGL Viewer: Web-based molecular graphics for large complexes. Bioinformatics, 2018, 34(21), 3755-3758.
[http://dx.doi.org/10.1093/bioinformatics/bty419] [PMID: 29850778]
[118]
RCSB Protein Data Bank. https://www.rcsb.org/structure/ 4AWM (Accessed on Nov 17, 2020).

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