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Current Medicinal Chemistry


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

Review Article

Focusing on the Influenza Virus Polymerase Complex: Recent Progress in Drug Discovery and Assay Development

Author(s): Jiantao Zhang, Yanmei Hu, Rami Musharrafieh, Hang Yin and Jun Wang*

Volume 26, Issue 13, 2019

Page: [2243 - 2263] Pages: 21

DOI: 10.2174/0929867325666180706112940

Price: $65


Influenza viruses are severe human pathogens that pose persistent threat to public health. Each year more people die of influenza virus infection than that of breast cancer. Due to the limited efficacy associated with current influenza vaccines, as well as emerging drug resistance from small molecule antiviral drugs, there is a clear need to develop new antivirals with novel mechanisms of action. The influenza virus polymerase complex has become a promising target for the development of the next-generation of antivirals for several reasons. Firstly, the influenza virus polymerase, which forms a heterotrimeric complex that consists of PA, PB1, and PB2 subunits, is highly conserved. Secondly, both individual polymerase subunit (PA, PB1, and PB2) and inter-subunit interactions (PA-PB1, PB1- PB2) represent promising drug targets. Lastly, growing insight into the structure and function of the polymerase complex has spearheaded the structure-guided design of new polymerase inhibitors. In this review, we highlight recent progress in drug discovery and assay development targeting the influenza virus polymerase complex and discuss their therapeutic potentials.

Keywords: Influenza, polymerase, ribonucleoprotein, PA, PB1, PB2.

Flu Symptoms & Complications. Centers for disease control and prevention. Available at:. [Accessed date: February 20th, 2018].
Rothberg, M.B.; Haessler, S.D.; Brown, R.B. Complications of viral influenza. Am. J. Med., 2008, 121(4), 258-264. []. [PMID: 18374680].
Molinari, N.A.; Ortega-Sanchez, I.R.; Messonnier, M.L.; Thompson, W.W.; Wortley, P.M.; Weintraub, E.; Bridges, C.B. The annual impact of seasonal influenza in the US: Measuring disease burden and costs. Vaccine, 2007, 25(27), 5086-5096. []. [PMID: 17544181].
Palese, P. Influenza: old and new threats. Nat. Med., 2004, 10(12)(Suppl.), S82-S87. []. [PMID: 15577936].
Monto, A.S.; Webster, R.G. Textbook of Influenza, 2013, 20-34.
Lamb, R.A.; Krug, R.M. Orthomyxoviridae: The viruses and their replication. In: n D. M. Knipe, P. M. Howley, & B. N. Fields (Eds.), Fields Virology Philadelphia:; Lippincott-Raven Press, 1996.
Su, S.; Bi, Y.; Wong, G.; Gray, G.C.; Gao, G.F.; Li, S. Epidemiology, evolution, and recent outbreaks of avian influenza virus in China. J. Virol., 2015, 89(17), 8671-8676. []. [PMID: 26063419].
Koutsakos, M.; Nguyen, T.H.; Barclay, W.S.; Kedzierska, K. Knowns and unknowns of influenza B viruses. Future Microbiol., 2016, 11(1), 119-135. []. [PMID: 26684590].
van de Sandt, C.E.; Bodewes, R.; Rimmelzwaan, G.F.; de Vries, R.D. Influenza B viruses: not to be discounted. Future Microbiol., 2015, 10(9), 1447-1465. []. [PMID: 26357957].
Krammer, F.; Palese, P. Advances in the development of influenza virus vaccines. Nat. Rev. Drug Discov., 2015, 14(3), 167-182. []. [PMID: 25722244].
Bouvier, N.M.; Palese, P. The biology of influenza viruses. Vaccine, 2008, 26(Suppl. 4), D49-D53. []. [PMID: 19230160].
Hurt, A.C. The epidemiology and spread of drug resistant human influenza viruses. Curr. Opin. Virol., 2014, 8(0), 22-29. []. [PMID: 24866471].
Eisfeld, A.J.; Neumann, G.; Kawaoka, Y. At the centre: Influenza A virus ribonucleoproteins. Nat. Rev. Microbiol., 2015, 13(1), 28-41. []. [PMID: 25417656].
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. []. [PMID: 28115197].
Li, F.; Ma, C.; Wang, J. Inhibitors targeting the influenza virus hemagglutinin. Curr. Med. Chem., 2015, 22(11), 1361-1382. []. [PMID: 25723505].
Wang, J.; Qiu, J.X.; Soto, C.; DeGrado, W.F. Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virus. Curr. Opin. Struct. Biol., 2011, 21(1), 68-80. []. [PMID: 21247754].
Reich, S.; Guilligay, D.; Pflug, A.; Malet, H.; Berger, I.; Crépin, T.; Hart, D.; Lunardi, T.; Nanao, M.; Ruigrok, R.W.; Cusack, S. Structural insight into cap-snatching and RNA synthesis by influenza polymerase. Nature, 2014, 516(7531), 361-366. []. [PMID: 25409151].
Key Facts About Seasonal Flu Vaccine Centers for disease control and prevention., Available at:. [Accessed date: February 20th, 2018].
Osterholm, M.T.; Kelley, N.S.; Sommer, A.; Belongia, E.A. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect. Dis., 2012, 12(1), 36-44. []. [PMID: 22032844].
Flannery, B.; Thaker, S.N.; Clippard, J.; Monto, A.S.; Ohmit, S.E.; Zimmerman, R.K.; Nowalk, M.P.; Gaglani, M.; Jackson, M.L.; Jackson, L.A.; Belongia, E.A.; McLean, H.Q.; Berman, L.; Foust, A.; Sessions, W.; Spencer, S.; Fry, A.M. Centers for Disease Control and Prevention (CDC). Interim estimates of 2013-14 seasonal influenza vaccine effectiveness - United States, February 2014. MMWR Morb. Mortal. Wkly. Rep., 2014, 63(7), 137-142. [PMID: 24553196].
Houser, K.; Subbarao, K. Influenza vaccines: Challenges and solutions. Cell Host Microbe, 2015, 17(3), 295-300. []. [PMID: 25766291].
Ison, M.G. Clinical use of approved influenza antivirals: therapy and prophylaxis. Influenza Other Respir. Viruses, 2013, 7(Suppl. 1), 7-13. []. [PMID: 23279892].
Koszalka, P.; Tilmanis, D.; Hurt, A.C. Influenza antivirals currently in late-phase clinical trial. Influenza Other Respir. Viruses, 2017, 11(3), 240-246. []. [PMID: 28146320].
Wang, J.; Li, F.; Ma, C. Recent progress in designing inhibitors that target the drug-resistant M2 proton channels from the influenza A viruses. Biopolymers, 2015, 104(4), 291-309. []. [PMID: 25663018].
Wang, J. M2 as a target to combat influenza drug resistance: What does the evidence say? Future Virol., 2016, 11(1), 1-4. [].
Loregian, A.; Mercorelli, B.; Nannetti, G.; Compagnin, C.; Palù, G. Antiviral strategies against influenza virus: Towards new therapeutic approaches. Cell. Mol. Life Sci., 2014, 71(19), 3659-3683. []. [PMID: 24699705].
Sheu, T.G.; Fry, A.M.; Garten, R.J.; Deyde, V.M.; Shwe, T.; Bullion, L.; Peebles, P.J.; Li, Y.; Klimov, A.I.; Gubareva, L.V. Dual resistance to adamantanes and oseltamivir among seasonal influenza A(H1N1) viruses: 2008-2010. J. Infect. Dis., 2011, 203(1), 13-17. []. [PMID: 21148491].
Moscona, A. Global transmission of oseltamivir-resistant influenza. N. Engl. J. Med., 2009, 360(10), 953-956. []. [PMID: 19258250].
Grigoryan, G.; Moore, D.T.; DeGrado, W.F. Transmembrane communication: general principles and lessons from the structure and function of the M2 proton channel, K+ channels, and integrin receptors. Annu. Rev. Biochem., 2011, 80(1), 211-237. []. [PMID: 21548783].
Baz, M.; Abed, Y.; Papenburg, J.; Bouhy, X.; Hamelin, M.E.; Boivin, G. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. N. Engl. J. Med., 2009, 361(23), 2296-2297. []. [PMID: 19907034].
Okomo-Adhiambo, M.; Fry, A.M.; Su, S.; Nguyen, H.T.; Elal, A.A.; Negron, E.; Hand, J.; Garten, R.J.; Barnes, J.; Xiyan, X.; Villanueva, J.M.; Gubareva, L.V.; Group, U.S. Oseltamivir-resistant influenza A(H1N1)pdm09 viruses, United States, 2013-14. Emerg. Infect. Dis., 2015, 21(1), 136-141. []. [PMID: 25532050].
Renaud, C.; Kuypers, J.; Englund, J.A. Emerging oseltamivir resistance in seasonal and pandemic influenza A/H1N1. J. Clin. Virol., 2011, 52(2), 70-78. []. [PMID: 21684202].
Govorkova, E.A. Consequences of resistance: in vitro fitness, in vivo infectivity, and transmissibility of oseltamivir-resistant influenza A viruses. Influenza Other Respir. Viruses, 2013, 7(Suppl. 1), 50-57. []. [PMID: 23279897].
Hsu, J.; Santesso, N.; Mustafa, R.; Brozek, J.; Chen, Y.L.; Hopkins, J.P.; Cheung, A.; Hovhannisyan, G.; Ivanova, L.; Flottorp, S.A.; Saeterdal, I.; Wong, A.D.; Tian, J.; Uyeki, T.M.; Akl, E.A.; Alonso-Coello, P.; Smaill, F.; Schünemann, H.J. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann. Intern. Med., 2012, 156(7), 512-524. []. [PMID: 22371849].
Yang, J.; Li, M.; Shen, X.; Liu, S. Influenza A virus entry inhibitors targeting the hemagglutinin. Viruses, 2013, 5(1), 352-373. []. [PMID: 23340380].
Kadam, R.U.; Wilson, I.A. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc. Natl. Acad. Sci. USA, 2017, 114(2), 206-214. []. [PMID: 28003465].
Leneva, I.A.; Russell, R.J.; Boriskin, Y.S.; Hay, A.J. Characteristics of arbidol-resistant mutants of influenza virus: Implications for the mechanism of anti-influenza action of arbidol. Antiviral Res., 2009, 81(2), 132-140. []. [PMID: 19028526].
Moss, R.B.; Hansen, C.; Sanders, R.L.; Hawley, S.; Li, T.; Steigbigel, R.T. A phase II study of DAS181, a novel host directed antiviral for the treatment of influenza infection. J. Infect. Dis., 2012, 206(12), 1844-1851. []. [PMID: 23045618].
Rossignol, J.F. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res., 2014, 110, 94-103. []. [PMID: 25108173].
Rossignol, J.F.; La Frazia, S.; Chiappa, L.; Ciucci, A.; Santoro, M.G. Thiazolides, a new class of anti-influenza molecules targeting viral hemagglutinin at the post-translational level. J. Biol. Chem., 2009, 284(43), 29798-29808. []. [PMID: 19638339].
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. []. [PMID: 27569399].
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. []. [PMID: 24084488].
Sangawa, H.; Komeno, T.; Nishikawa, H.; Yoshida, A.; Takahashi, K.; Nomura, N.; Furuta, Y. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob. Agents Chemother., 2013, 57(11), 5202-5208. []. [PMID: 23917318].
Baranovich, T.; Wong, S-S.; Armstrong, J.; Marjuki, H.; Webby, R.J.; Webster, R.G.; Govorkova, E.A. T-705 (favipiravir) induces lethal mutagenesis in influenza A H1N1 viruses in vitro. J. Virol., 2013, 87(7), 3741-3751. []. [PMID: 23325689].
Te Velthuis, A.J.; Fodor, E. Influenza virus RNA polymerase: Insights into the mechanisms of viral RNA synthesis. Nat. Rev. Microbiol., 2016, 14(8), 479-493. []. [PMID: 27396566].
Boivin, S.; Cusack, S.; Ruigrok, R.W.; Hart, D.J. Influenza A virus polymerase: Structural insights into replication and host adaptation mechanisms. J. Biol. Chem., 2010, 285(37), 28411-28417. []. [PMID: 20538599].
Hu, Y. EDITORIAL: Advances in developing versatile tools for the discovery of novel therapeutics. Curr. Top. Med. Chem., 2017, 17(20), 2233-2234. []. [PMID: 28799501].
Hu, Y.; Sneyd, H.; Dekant, R.; Wang, J.; Influenza, A. Influenza A virus nucleoprotein: A highly conserved multi-functional viral protein as a hot antiviral drug target. Curr. Top. Med. Chem., 2017, 17(20), 2271-2285. []. [PMID: 28240183].
Beyleveld, G.; White, K.M.; Ayllon, J.; Shaw, M.L. New-generation screening assays for the detection of anti-influenza compounds targeting viral and host functions. Antiviral Res., 2013, 100(1), 120-132. []. [PMID: 23933115].
Luytjes, W.; Krystal, M.; Enami, M.; Parvin, J.D.; Palese, P. Amplification, expression, and packaging of foreign gene by influenza virus. Cell, 1989, 59(6), 1107-1113. []. [PMID: 2598262].
Seong, B.L.; Brownlee, G.G. A new method for reconstituting influenza polymerase and RNA in vitro: A study of the promoter elements for cRNA and vRNA synthesis in vitro and viral rescue in vivo. Virology, 1992, 186(1), 247-260. []. [PMID: 1727600].
Neumann, G.; Hobom, G. Mutational analysis of influenza virus promoter elements in vivo. J. Gen. Virol., 1995, 76(Pt 7), 1709-1717. []. [PMID: 9049376].
Lutz, A.; Dyall, J.; Olivo, P.D.; Pekosz, A. Virus-inducible reporter genes as a tool for detecting and quantifying influenza A virus replication. J. Virol. Methods, 2005, 126(1-2), 13-20. []. [PMID: 15847914].
Ozawa, M.; Shimojima, M.; Goto, H.; Watanabe, S.; Hatta, Y.; Kiso, M.; Furuta, Y.; Horimoto, T.; Peters, N.R.; Hoffmann, F.M.; Kawaoka, Y. A cell-based screening system for influenza A viral RNA transcription/replication inhibitors. Sci. Rep., 2013, 3, 1106. []. [PMID: 23346363].
Hoffmann, H-H.; Kunz, A.; Simon, V.A.; Palese, P.; Shaw, M.L. Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis. Proc. Natl. Acad. Sci. USA, 2011, 108(14), 5777-5782. []. [PMID: 21436031].
Hoffmann, H.H.; Palese, P.; Shaw, M.L. Modulation of influenza virus replication by alteration of sodium ion transport and protein kinase C activity. Antiviral Res., 2008, 80(2), 124-134. []. [PMID: 18585796].
Wang, Z.; Zhao, F.; Gao, Q.; Liu, Z.; Zhang, Y.; Li, X.; Li, Y.; Ma, W.; Deng, T.; Zhang, Z.; Cen, S. Establishment of a high-throughput assay to monitor influenza A virus RNA transcription and replication. PLoS One, 2015, 10(7)e0133558 []. [PMID: 26196128].
Karlas, A.; Machuy, N.; Shin, Y.; Pleissner, K.P.; Artarini, A.; Heuer, D.; Becker, D.; Khalil, H.; Ogilvie, L.A.; Hess, S.; Mäurer, A.P.; Müller, E.; Wolff, T.; Rudel, T.; Meyer, T.F. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature, 2010, 463(7282), 818-822. []. [PMID: 20081832].
Prusty, B.K.; Karlas, A.; Meyer, T.F.; Rudel, T. Genome-wide RNAi screen for viral replication in mammalian cell culture. Methods Mol. Biol., 2011, 721, 383-395. []. [PMID: 21431699].
Shapira, S.D.; Gat-Viks, I.; Shum, B.O.; Dricot, A.; de Grace, M.M.; Wu, L.; Gupta, P.B.; Hao, T.; Silver, S.J.; Root, D.E.; Hill, D.E.; Regev, A.; Hacohen, N. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell, 2009, 139(7), 1255-1267. []. [PMID: 20064372].
Hooker, L.; Strong, R.; Adams, R.; Handa, B.; Merrett, J.H.; Martin, J.A.; Klumpp, K. A sensitive, single-tube assay to measure the enzymatic activities of influenza RNA polymerase and other poly(A) polymerases: Application to kinetic and inhibitor analysis. Nucleic Acids Res., 2001, 29(13), 2691-2698. []. [PMID: 11433013].
Newcomb, L.L.; Kuo, R.L.; Ye, Q.; Jiang, Y.; Tao, Y.J.; Krug, R.M. Interaction of the influenza a virus nucleocapsid protein with the viral RNA polymerase potentiates unprimed viral RNA replication. J. Virol., 2009, 83(1), 29-36. []. [PMID: 18945782].
Glickman, J.F.; Schmid, A.; Ferrand, S. Scintillation proximity assays in high-throughput screening. Assay Drug Dev. Technol., 2008, 6(3), 433-455. []. [PMID: 18593378].
Sidwell, R.W.; Smee, D.F. In vitro and in vivo assay systems for study of influenza virus inhibitors. Antiviral Res., 2000, 48(1), 1-16. []. [PMID: 11080536].
Reich, S.; Guilligay, D.; Cusack, S. An in vitro fluorescence based study of initiation of RNA synthesis by influenza B polymerase. Nucleic Acids Res., 2017, 45(6), 3353-3368. [PMID: 28126917].
Ju, H.; Zhang, J.; Huang, B.; Kang, D.; Huang, B.; Liu, X.; Zhan, P. Inhibitors of Influenza Virus Polymerase Acidic (PA) Endonuclease: Contemporary developments and perspectives. J. Med. Chem., 2017, 60(9), 3533-3551. []. [PMID: 28118010].
Su, M.; Tan, J.; Lin, C.Y. Development of HIV-1 integrase inhibitors: Recent molecular modeling perspectives. Drug Discov. Today, 2015, 20(11), 1337-1348. []. [PMID: 26220090].
Song, M.S.; Kumar, G.; Shadrick, W.R.; Zhou, W.; Jeevan, T.; Li, Z.; Slavish, P.J.; Fabrizio, T.P.; Yoon, S.W.; Webb, T.R.; Webby, R.J.; White, S.W. Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor. Proc. Natl. Acad. Sci. USA, 2016, 113(13), 3669-3674. []. [PMID: 26976575].
Thierry, E.; Deprez, E.; Delelis, O. Different pathways leading to integrase inhibitors resistance. Front. Microbiol., 2017, 7, 2165. []. [PMID: 28123383].
Walsh, C.T.; Wencewicz, T.A. Prospects for new antibiotics: A molecule-centered perspective. J. Antibiot. , 2014, 67(1), 7-22. []. [PMID: 23756684].
Jones, J.C.; Marathe, B.M.; Vogel, P.; Gasser, R.; Najera, I.; Govorkova, E.A. The PA endonuclease inhibitor RO-7 protects mice from lethal challenge with influenza A or B viruses. Antimicrob. Agents Chemother., 2017, 61(5), 2460-2416. []. [PMID: 28193653].
Jones, J.C.; Marathe, B.M.; Lerner, C.; Kreis, L.; Gasser, R.; Pascua, P.N.; Najera, I.; Govorkova, E.A. A novel endonuclease inhibitor exhibits broad-spectrum anti-influenza virus activity in vitro. Antimicrob. Agents Chemother., 2016, 60(9), 5504-5514. []. [PMID: 27381402].
Carcelli, M.; Rogolino, D.; Gatti, A.; De Luca, L.; Sechi, M.; Kumar, G.; White, S.W.; Stevaert, A.; Naesens, L. N-acylhydrazone inhibitors of influenza virus PA endonuclease with versatile metal binding modes. Sci. Rep., 2016, 6, 31500. []. [PMID: 27510745].
Yuan, S.; Chu, H.; Singh, K.; Zhao, H.; Zhang, K.; Kao, R.Y.; Chow, B.K.; 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. []. [PMID: 26956222].
Credille, C.V.; Chen, Y.; Cohen, S.M. Fragment-based identification of influenza endonuclease inhibitors. J. Med. Chem., 2016, 59(13), 6444-6454. []. [PMID: 27291165].
Yuan, S.; Zhang, N.; Singh, K.; Shuai, H.; Chu, H.; Zhou, J.; Chow, B.K.; Zheng, B.J. Cross-protection of influenza A virus infection by a DNA aptamer targeting the PA endonuclease domain. Antimicrob. Agents Chemother., 2015, 59(7), 4082-4093. []. [PMID: 25918143].
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 []. [PMID: 22876176].
Noble, E.; Cox, A.; Deval, J.; Kim, B. Endonuclease substrate selectivity characterized with full-length PA of influenza A virus polymerase. Virology, 2012, 433(1), 27-34. []. [PMID: 22841552].
Baughman, B.M.; Jake Slavish, P.; DuBois, R.M.; Boyd, V.A.; White, S.W.; Webb, T.R. Identification of influenza endonuclease inhibitors using a novel fluorescence polarization assay. ACS Chem. Biol., 2012, 7(3), 526-534. []. [PMID: 22211528].
Kepp, O.; Galluzzi, L.; Lipinski, M.; Yuan, J.; Kroemer, G. Cell death assays for drug discovery. Nat. Rev. Drug Discov., 2011, 10(3), 221-237. []. [PMID: 21358741].
Pautus, S.; Sehr, P.; Lewis, J.; Fortuné, A.; Wolkerstorfer, A.; Szolar, O.; Guilligay, D.; Lunardi, T.; Décout, J.L.; Cusack, S. New 7-methylguanine derivatives targeting the influenza polymerase PB2 cap-binding domain. J. Med. Chem., 2013, 56(21), 8915-8930. []. [PMID: 24134208].
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. []. [PMID: 25019388].
Farmer, L.J.; Clark, M.P.; Boyd, M.J.; Perola, E.; Jones, S.M.; Tsai, A.; Jacobs, M.D.; Bandarage, U.K.; Ledeboer, M.W.; Wang, T.; Deng, H.; Ledford, B.; Gu, W.; Duffy, J.P.; Bethiel, R.S.; Shannon, D.; Byrn, R.A.; Leeman, J.R.; Rijnbrand, R.; Bennett, H.B.; O’Brien, C.; Memmott, C.; Nti-Addae, K.; Bennani, Y.L.; Charifson, P.S. Discovery of novel, orally bioavailable β-amino acid azaindole inhibitors of influenza PB2. ACS Med. Chem. Lett., 2017, 8(2), 256-260. []. [PMID: 28197322].
Bandarage, U.K.; Clark, M.P.; Perola, E.; Gao, H.; Jacobs, M.D.; Tsai, A.; Gillespie, J.; Kennedy, J.M.; Maltais, F.; Ledeboer, M.W.; Davies, I.; Gu, W.; Byrn, R.A.; Nti Addae, K.; Bennett, H.; Leeman, J.R.; Jones, S.M.; O’Brien, C.; Memmott, C.; Bennani, Y.; Charifson, P.S. Novel 2-substituted 7-azaindole and 7-azaindazole analogues as potential antiviral agents for the treatment of influenza. ACS Med. Chem. Lett., 2017, 8(2), 261-265. []. [PMID: 28197323].
Yuan, S.; Chu, H.; Zhang, K.; Ye, J.; Singh, K.; Kao, R.Y.; Chow, B.K.; Zhou, J.; Zheng, B.J. A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication. J. Antimicrob. Chemother., 2016, 71(9), 2489-2497. []. [PMID: 27272726].
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. []. [PMID: 25547360].
Hatakeyama, D.; Shoji, M.; Yamayoshi, S.; Hirota, T.; Nagae, M.; Yanagisawa, S.; Nakano, M.; Ohmi, N.; Noda, T.; Kawaoka, Y.; Kuzuhara, T. A novel functional site in the PB2 subunit of influenza A virus essential for acetyl-CoA interaction, RNA polymerase activity, and viral replication. J. Biol. Chem., 2014, 289(36), 24980-24994. []. [PMID: 25063805].
Perales, B.; Ortín, J. The influenza A virus PB2 polymerase subunit is required for the replication of viral RNA. J. Virol., 1997, 71(2), 1381-1385. [PMID: 8995663].
Brownlee, G.G.; Sharps, J.L. The RNA polymerase of influenza A virus is stabilized by interaction with its viral RNA promoter. J. Virol., 2002, 76(14), 7103-7113. []. [PMID: 12072510].
Fodor, E.; Crow, M.; Mingay, L.J.; Deng, T.; Sharps, J.; Fechter, P.; Brownlee, G.G. A single amino acid mutation in the PA subunit of the influenza virus RNA polymerase inhibits endonucleolytic cleavage of capped RNAs. J. Virol., 2002, 76(18), 8989-9001. []. [PMID: 12186883].
Perez, D.R.; Donis, R.O. Functional analysis of PA binding by influenza A virus PB1: Effects on polymerase activity and viral infectivity. J. Virol., 2001, 75(17), 8127-8136. []. [PMID: 11483758].
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. []. [PMID: 17494067].
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. []. [PMID: 25409142].
Krug, R.M.; Aramini, J.M. Emerging antiviral targets for influenza A virus. Trends Pharmacol. Sci., 2009, 30(6), 269-277. []. [PMID: 19428126].
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. []. [PMID: 27046062].
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. []. [PMID: 22474359].
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. []. [PMID: 25856229].
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. []. [PMID: 24314669].
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. []. [PMID: 24285596].
Trist, I.M.; 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. []. [PMID: 26924568].
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. []. [PMID: 18615018].
Yuan, S.; Chu, H.; Zhao, H.; Zhang, K.; Singh, K.; Chow, B.K.; Kao, R.Y.; 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. []. [PMID: 26593979].
Yuan, S.; Chu, H.; Ye, J.; Singh, K.; Ye, Z.; Zhao, H.; Kao, R.Y.; Chow, B.K.; Zhou, J.; Zheng, B.J. Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface. Antiviral Res., 2017, 137, 58-66. []. [PMID: 27840201].
Pérez, D.R.; Donis, R.O.A. 48-amino-acid region of influenza A virus PB1 protein is sufficient for complex formation with PA. J. Virol., 1995, 69(11), 6932-6939. [PMID: 7474111].
González, S.; Zürcher, T.; Ortín, J. Identification of two separate domains in the influenza virus PB1 protein involved in the interaction with the PB2 and PA subunits: A model for the viral RNA polymerase structure. Nucleic Acids Res., 1996, 24(22), 4456-4463. []. [PMID: 8948635].
Zürcher, T.; de la Luna, S.; Sanz-Ezquerro, J.J.; Nieto, A.; Ortín, J. Mutational analysis of the influenza virus A/Victoria/3/75 PA protein: Studies of interaction with PB1 protein and identification of a dominant negative mutant. J. Gen. Virol., 1996, 77(Pt 8), 1745-1749. []. [PMID: 8760421].
Toyoda, T.; Adyshev, D.M.; Kobayashi, M.; Iwata, A.; Ishihama, A. Molecular assembly of the influenza virus RNA polymerase: Determination of the subunit-subunit contact sites. J. Gen. Virol., 1996, 77(Pt 9), 2149-2157. []. [PMID: 8811014].
Ohtsu, Y.; Honda, Y.; Sakata, Y.; Kato, H.; Toyoda, T. Fine mapping of the subunit binding sites of influenza virus RNA polymerase. Microbiol. Immunol., 2002, 46(3), 167-175. []. [PMID: 12008925].
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. []. [PMID: 17121807].
Hemerka, J.N.; Wang, D.; Weng, Y.; Lu, W.; Kaushik, R.S.; Jin, J.; Harmon, A.F.; Li, F. Detection and characterization of influenza A virus PA-PB2 interaction through a bimolecular fluorescence complementation assay. J. Virol., 2009, 83(8), 3944-3955. []. [PMID: 19193801].
Deng, Q.; Wang, D.; Xiang, X.; Gao, X.; Hardwidge, P.R.; Kaushik, R.S.; Wolff, T.; Chakravarty, S.; Li, F. Application of a split luciferase complementation assay for the detection of viral protein-protein interactions. J. Virol. Methods, 2011, 176(1-2), 108-111. []. [PMID: 21645548].
Wunderlich, K.; Juozapaitis, M.; Ranadheera, C.; Kessler, U.; Martin, A.; Eisel, J.; Beutling, U.; Frank, R.; Schwemmle, M. Identification of high-affinity PB1-derived peptides with enhanced affinity to the PA protein of influenza A virus polymerase. Antimicrob. Agents Chemother., 2011, 55(2), 696-702. []. [PMID: 21135188].
Li, C.; Wang, Z.; Cao, Y.; Wang, L.; Ji, J.; Chen, Z.; Deng, T.; Jiang, T.; Cheng, G.; Qin, F.X. Screening for novel small-molecule inhibitors targeting the assembly of influenza virus polymerase complex by a bimolecular luminescence complementation-based reporter system. J. Virol., 2017, 91(5), 2282-16. []. [PMID: 28031371].
Shekhawat, S.S.; Ghosh, I. Split-protein systems: Beyond binary protein-protein interactions. Curr. Opin. Chem. Biol., 2011, 15(6), 789-797. []. [PMID: 22070901].

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