Structure and Activities of the NS1 Influenza Protein and Progress in the Development of Small-Molecule Drugs
Abstract
:1. Introduction
2. Structure of the NS1 Protein
3. Function of NS1 in Infected Cells
3.1. Translation of Viral mRNA
3.2. Responses of the Human Immune System
3.3. OAS and PKR
3.4. The Host RNAi Pathway and Apoptotic Response
3.5. PI3K Signaling Pathway
4. Virulence of NS1 in Influenza A Viruses
5. Antiviral Compounds Targeting NS1
5.1. Small Molecules Targeting NS1
5.2. Other Small Molecules Targeting Influenza Virus A
6. Conclusions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Thompson, W.W.; Comanor, L.; Shay, D.K. Epidemiology of Seasonal Influenza: Use of Surveillance Data and Statistical Models to Estimate the Burden of Disease. J. Infect. Dis. 2006, 194, S82–S91. [Google Scholar] [CrossRef] [Green Version]
- Taubenberger, J.K.; Morens, D.M. 1918 Influenza: The mother of all pandemics. Emerg. Infect. Dis. 2006, 12, 69–79. [Google Scholar] [CrossRef]
- Gambotto, A.; Barratt-Boyes, S.M.; de Jong, M.D.; Neumann, G.; Kawaoka, Y. Human infection with highly pathogenic H5N1 influenza virus. Lancet 2008, 371, 1464–1475. [Google Scholar] [CrossRef]
- Pada, S.; Tambyah, P.A. Overview/reflections on the 2009 H1N1 pandemic. Microbes Infect. 2011, 13, 470–478. [Google Scholar] [CrossRef]
- Shaw, M.; Palese, P. Orthomyxoviridae: The viruses and their replication. Fields Virol. 2007, 5, 1647–1689. [Google Scholar]
- Horimoto, T.; Kawaoka, Y. Influenza: Lessons from past pandemics, warnings from current incidents. Nat. Rev. Genet. 2005, 3, 591–600. [Google Scholar] [CrossRef]
- Taubenberger, J.K.; Morens, D.M. The Pathology of Influenza Virus Infections. Annu. Rev. Pathol. Mech. Dis. 2008, 3, 499–522. [Google Scholar] [CrossRef]
- Smith, D.B.; Gaunt, E.R.; Digard, P.; Templeton, K.; Simmonds, P. Detection of influenza C virus but not influenza D virus in Scottish respiratory samples. J. Clin. Virol. 2016, 74, 50–53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guo, Y.J.; Jin, F.G.; Wang, P.; Wang, M.; Zhu, J.M. Isolation of Influenza C Virus from Pigs and Experimental Infection of Pigs with Influenza C Virus. J. Gen. Virol. 1983, 64, 177–182. [Google Scholar] [CrossRef] [PubMed]
- Moscona, A. Neuraminidase Inhibitors for Influenza. N. Engl. J. Med. 2005, 353, 1363–1373. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hayden, F.G.; Sugaya, N.; Hirotsu, N.; Lee, N.; De Jong, M.D.; Hurt, A.C.; Ishida, T.; Sekino, H.; Yamada, K.; Portsmouth, S.; et al. Baloxavir Marboxil for Uncomplicated Influenza in Adults and Adolescents. N. Engl. J. Med. 2018, 379, 913–923. [Google Scholar] [CrossRef]
- Hayden, F.G.; Pavia, A.T. Antiviral Management of Seasonal and Pandemic Influenza. J. Infect. Dis. 2006, 194, S119–S126. [Google Scholar] [CrossRef]
- Ayllon, J.; García-Sastre, A. The NS1 protein: A multitasking virulence factor. In Influenza Pathogenesis and Control; Springer: Cham, Switzerland, 2014; Volume II, pp. 73–107. [Google Scholar] [CrossRef]
- Krug, R.M. Functions of the influenza A virus NS1 protein in antiviral defense. Curr. Opin. Virol. 2015, 12, 1–6. [Google Scholar] [CrossRef] [Green Version]
- Basler, C.F.; Aguilar, P.V. Progress in identifying virulence determinants of the 1918 H1N1 and the Southeast Asian H5N1 influenza A viruses. Antivir. Res. 2008, 79, 166–178. [Google Scholar] [CrossRef] [Green Version]
- Donelan, N.R.; Basler, C.F.; García-Sastre, A. A recombinant influenza A virus expressing an RNA-binding-defective NS1 protein induces high levels of beta interferon and is attenuated in mice. J. Virol. 2003, 77, 13257–13266. [Google Scholar] [CrossRef] [Green Version]
- Egorov, A.; Brandt, S.; Sereinig, S.; Romanova, J.; Ferko, B.; Katinger, D.; Grassauer, A.; Alexandrova, G.; Katinger, H.; Muster, T. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J. Virol. 1998, 72, 6437–6441. [Google Scholar] [CrossRef] [Green Version]
- García-Sastre, A.; Egorov, A.; Matassova, D.; Brandtbc, S.; Levy, D.E.; Durbin, J.E.; Palese, P.; Musterbc, T. Influenza A Virus Lacking the NS1 Gene Replicates in Interferon-Deficient Systems. Virology 1998, 252, 324–330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jackson, D.; Hossain, J.; Hickman, D.; Perez, D.R.; Lamb, R.A. A new influenza virus virulence determinant: The NS1 protein four C-terminal residues modulate pathogenicity. Proc. Natl. Acad. Sci. USA 2008, 105, 4381–4386. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wolstenholme, A.; Barrett, T.; Nichol, S.; Mahy, B. Influenza virus-specific RNA and protein syntheses in cells infected with temperature-sensitive mutants defective in the genome segment encoding nonstructural proteins. J. Virol. 1980, 35, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yin, C.; Khan, J.A.; Swapna, G.V.T.; Ertekin, A.; Krug, R.M.; Tong, L.; Montelione, G.T. Conserved Surface Features Form the Double-stranded RNA Binding Site of Non-structural Protein 1 (NS1) from Influenza A and B Viruses. J. Biol. Chem. 2007, 282, 20584–20592. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hale, B.G. Conformational plasticity of the influenza A virus NS1 protein. J. Gen. Virol. 2014, 95, 2099–2105. [Google Scholar] [CrossRef] [PubMed]
- Chien, C.; Tejero, R.; Huang, Y.; Zimmerman, D.E.; Ríos, C.B.; Krug, R.M.; Montelione, G.T. A novel RNA-binding motif in influenza A virus non-structural protein 1. Nat. Struct. Biol. 1997, 4, 891–895. [Google Scholar] [CrossRef]
- Wang, W.; Riedel, K.; Lynch, P.; Chien, C.-Y.; Montelione, G.T.; Krug, R.M. RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. RNA 1999, 5, 195–205. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Carrillo, B.; Choi, J.-M.; Bornholdt, Z.A.; Sankaran, B.; Rice, A.P.; Prasad, B.V.V. The Influenza A Virus Protein NS1 Displays Structural Polymorphism. J. Virol. 2014, 88, 4113–4122. [Google Scholar] [CrossRef] [Green Version]
- Chien, C.-y.; Xu, Y.; Xiao, R.; Aramini, J.M.; Sahasrabudhe, P.V.; Krug, R.M.; Montelione, G.T. Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: Evidence for a novel RNA-binding mode. Biochemistry 2004, 43, 1950–1962. [Google Scholar] [CrossRef]
- Hatada, E.; Fukuda, R. Binding of influenza A virus NS1 protein to dsRNA in vitro. J. Gen. Virol. 1992, 73, 3325–3329. [Google Scholar] [CrossRef]
- Xia, S.; Monzingo, A.F.; Robertus, J.D. Structure of NS1A effector domain from the influenza A/Udorn/72 virus. Acta Crystallogr. Sect. D Biol. Crystallogr. 2008, 65, 11–17. [Google Scholar] [CrossRef]
- Mibayashi, M.; Martínez-Sobrido, L.; Loo, Y.-M.; Cárdenas, W.B.; Gale, M.; García-Sastre, A. Inhibition of Retinoic Acid-Inducible Gene I-Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A Virus. J. Virol. 2006, 81, 514–524. [Google Scholar] [CrossRef] [Green Version]
- Chen, Z.; Li, Y.; Krug, R.M. Influenza A virus NS1 protein targetspoly (A)-binding protein II of the cellular 3′-end processing machinery. EMBO J. 1999, 18, 2273–2283. [Google Scholar] [CrossRef] [Green Version]
- Tan, S.-L.; Katze, M.G. Biochemical and Genetic Evidence for Complex Formation Between the Influenza A Virus NS1 Protein and the Interferon-induced PKR Protein Kinase. J. Interf. Cytokine Res. 1998, 18, 757–766. [Google Scholar] [CrossRef] [PubMed]
- Burgui, I.; Aragón, T.; Ortín, J.; Nieto, A. PABP1 and eIF4GI associate with influenza virus NS1 protein in viral mRNA translation initiation complexes. J. Gen. Virol. 2003, 84, 3263–3274. [Google Scholar] [CrossRef]
- Nemeroff, M.E.; Barabino, S.M.; Li, Y.; Keller, W.; Krug, R.M. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′ end formation of cellular pre-mRNAs. Mol. Cell 1998, 1, 991–1000. [Google Scholar] [CrossRef]
- Aramini, J.M.; Hamilton, K.; Ma, L.-C.; Swapna, G.V.T.; Leonard, P.G.; Ladbury, J.E.; Krug, R.M.; Montelione, G.T. 19F NMR Reveals Multiple Conformations at the Dimer Interface of the Nonstructural Protein 1 Effector Domain from Influenza A Virus. Structure 2014, 22, 515–525. [Google Scholar] [CrossRef] [Green Version]
- Aramini, J.M.; Ma, L.-C.; Zhou, L.; Schauder, C.M.; Hamilton, K.; Amer, B.R.; Mack, T.R.; Lee, H.-W.; Ciccosanti, C.T.; Zhao, L.; et al. Dimer interface of the effector domain of non-structural protein 1 from influenza A virus an interface with multiple functions. J. Biol. Chem. 2011, 286, 26050–26060. [Google Scholar] [CrossRef] [Green Version]
- Cheng, A.; Wong, S.M.; Yuan, Y.A. Structural basis for dsRNA recognition by NS1 protein of influenza A virus. Cell Res. 2008, 19, 187–195. [Google Scholar] [CrossRef]
- Hale, B.G.; Randall, R.E.; Ortín, J.; Jackson, D. The multifunctional NS1 protein of influenza A viruses. J. Gen. Virol. 2008, 89, 2359–2376. [Google Scholar] [CrossRef] [PubMed]
- Melén, K.; Kinnunen, L.; Fagerlund, R.; Ikonen, N.; Twu, K.Y.; Krug, R.M.; Julkunen, I. Nuclear and Nucleolar Targeting of Influenza A Virus NS1 Protein: Striking Differences between Different Virus Subtypes. J. Virol. 2007, 81, 5995–6006. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Y.; Yamakita, Y.; Krug, R.M. Regulation of a nuclear export signal by an adjacent inhibitory sequence: The effector domain of the influenza virus NS1 protein. Proc. Natl. Acad. Sci. USA 1998, 95, 4864–4869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Marión, R.M.; Aragón, T.; Beloso, A.; Nieto, A.; Ortín, J. The N-terminal half of the influenza virus NS1 protein is sufficient for nuclear retention of mRNA and enhancement of viral mRNA translation. Nucleic Acids Res. 1997, 25, 4271–4277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Aragón, T.; de la Luna, S.; Novoa, I.; Carrasco, L.; Ortín, J.; Nieto, A. Eukaryotic translation initiation factor 4GI is a cellular target for NS1 protein, a translational activator of influenza virus. Mol. Cell. Biol. 2000, 20, 6259–6268. [Google Scholar] [CrossRef]
- Falcón, A.M.; Fortes, P.; Marión, R.M.; Beloso, A.; Ortín, J. Interaction of influenza virus NS1 protein and the human hom-ologue of Staufen in vivo and in vitro. Nucleic Acids Res. 1999, 27, 2241–2247. [Google Scholar] [CrossRef]
- Xu, K.; Klenk, C.; Liu, B.; Keiner, B.; Cheng, J.; Zheng, B.-J.; Li, L.; Han, Q.; Wang, C.; Li, T.; et al. Modification of Nonstructural Protein 1 of Influenza A Virus by SUMO1. J. Virol. 2010, 85, 1086–1098. [Google Scholar] [CrossRef] [Green Version]
- Klemm, C.; Boergeling, Y.; Ludwig, S.; Ehrhardt, C. Immunomodulatory Nonstructural Proteins of Influenza A Viruses. Trends Microbiol. 2018, 26, 624–636. [Google Scholar] [CrossRef]
- Wang, X.; Li, M.; Zheng, H.; Muster, T.; Palese, P.; Beg, A.A.; García-Sastre, A. Influenza A virus NS1 protein prevents activation of NF-κB and induction of alpha/beta interferon. J. Virol. 2000, 74, 11566–11573. [Google Scholar] [CrossRef] [Green Version]
- Talon, J.; Horvath, C.M.; Polley, R.; Basler, C.F.; Muster, T.; Palese, P.; García-Sastre, A. Activation of Interferon Regulatory Factor 3 Is Inhibited by the Influenza A Virus NS1 Protein. J. Virol. 2000, 74, 7989–7996. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gack, M.U.; Albrecht, R.A.; Urano, T.; Inn, K.-S.; Huang, I.-C.; Carnero, E.; Farzan, M.; Inoue, S.; Jung, J.U.; García-Sastre, A. Influenza A Virus NS1 Targets the Ubiquitin Ligase TRIM25 to Evade Recognition by the Host Viral RNA Sensor RIG-I. Cell Host Microbe 2009, 5, 439–449. [Google Scholar] [CrossRef] [Green Version]
- Lu, Y.; Qian, X.-Y.; Krug, R.M. The influenza virus NS1 protein: A novel inhibitor of pre-mRNA splicing. Genes Dev. 1994, 8, 1817–1828. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Seo, S.H.; Hoffmann, E.; Webster, R.G. Lethal H5N1 influenza viruses escape host anti-viral cytokine responses. Nat. Med. 2002, 8, 950–954. [Google Scholar] [CrossRef] [PubMed]
- Steinman, R.M.; Hemmi, H. Dendritic Cells: Translating Innate to Adaptive Immunity. Curr. Top. Microbiol. Immunol. 2006, 311, 17–58. [Google Scholar] [CrossRef] [Green Version]
- Fernandez-Sesma, A.; Marukian, S.; Ebersole, B.J.; Kaminski, D.; Park, M.-S.; Yuen, T.; Sealfon, S.C.; García-Sastre, A.; Moran, T.M. Influenza Virus Evades Innate and Adaptive Immunity via the NS1 Protein. J. Virol. 2006, 80, 6295–6304. [Google Scholar] [CrossRef] [Green Version]
- Marazzi, I.; Ho, J.S.Y.; Kim, J.; Manicassamy, B.; Dewell, S.; Albrecht, R.A.; Seibert, C.W.; Schaefer, U.; Jeffrey, K.L.; Prinjha, R.K.; et al. Suppression of the antiviral response by an influenza histone mimic. Nat. Cell Biol. 2012, 483, 428–433. [Google Scholar] [CrossRef]
- Silverman, R.H. Viral encounters with 2′,5′-oligoadenylate synthetase and RNase L during the interferon antiviral response. J. Virol. 2007, 81, 12720–12729. [Google Scholar] [CrossRef] [Green Version]
- Min, J.-Y.; Krug, R.M. The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway. Proc. Natl. Acad. Sci. USA 2006, 103, 7100–7105. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Min, J.-Y.; Li, S.; Sen, G.C.; Krug, R.M. A site on the influenza A virus NS1 protein mediates both inhibition of PKR activation and temporal regulation of viral RNA synthesis. Virology 2007, 363, 236–243. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lu, Y.; Wambach, M.; Katze, M.G.; Krug, R.M. Binding of the Influenza Virus NS1 Protein to Double-Stranded RNA Inhibits the Activation of the Protein Kinase That Phosphorylates the eIF-2 Translation Initiation Factor. Virology 1995, 214, 222–228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, S.; Min, J.-Y.; Krug, R.M.; Sen, G.C. Binding of the influenza A virus NS1 protein to PKR mediates the inhibition of its activation by either PACT or double-stranded RNA. Virology 2006, 349, 13–21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, W.-X.; Li, H.; Lu, R.; Li, F.; Dus, M.; Atkinson, P.; Brydon, E.W.A.; Johnson, K.L.; García-Sastre, A.; Ball, L.A.; et al. Interferon antagonist proteins of influenza and vaccinia viruses are suppressors of RNA silencing. Proc. Natl. Acad. Sci. USA 2004, 101, 1350–1355. [Google Scholar] [CrossRef] [Green Version]
- Bucher, E.; Hemmes, H.; De Haan, P.; Goldbach, R.; Prins, M. The influenza A virus NS1 protein binds small interfering RNAs and suppresses RNA silencing in plants. J. Gen. Virol. 2004, 85, 983–991. [Google Scholar] [CrossRef] [PubMed]
- Kok, K.H.; Jin, D.-Y. Influenza A virus NS1 protein does not suppress RNA interference in mammalian cells. J. Gen. Virol. 2006, 87, 2639–2644. [Google Scholar] [CrossRef]
- Zhang, C.; Yang, Y.; Zhou, X.; Yang, Z.; Liu, X.; Cao, Z.; Song, H.; He, Y.; Huang, P. The NS1 protein of influenza a virus interacts with heat shock protein Hsp90 in human alveolar basal epithelial cells: Implication for virus-induced apoptosis. Virol. J. 2011, 8, 181. [Google Scholar] [CrossRef] [Green Version]
- Ehrhardt, C.; Marjuki, H.; Wolff, T.; Nürnberg, B.; Planz, O.; Pleschka, S.; Ludwig, S. Bivalent role of the phosphatidylinositol-3-kinase (PI3K) during influenza virus infection and host cell defence. Cell. Microbiol. 2006, 8, 1336–1348. [Google Scholar] [CrossRef]
- Ehrhardt, C.; Wolff, T.; Pleschka, S.; Planz, O.; Beermann, W.; Bode, J.G.; Schmolke, M.; Ludwig, S. Influenza A Virus NS1 Protein Activates the PI3K/Akt Pathway To Mediate Antiapoptotic Signaling Responses. J. Virol. 2007, 81, 3058–3067. [Google Scholar] [CrossRef] [Green Version]
- Hale, B.G.; Jackson, D.; Chen, Y.-H.; Lamb, R.A.; Randall, R.E. Influenza A virus NS1 protein binds p85β and activates phosphatidylinositol-3-kinase signaling. Proc. Natl. Acad. Sci. USA 2006, 103, 14194–14199. [Google Scholar] [CrossRef] [Green Version]
- Heikkinen, L.S.; Kazlauskas, A.; Melén, K.; Wagner, R.; Ziegler, T.; Julkunen, I.; Saksela, K. Avian and 1918 Spanish influenza a virus NS1 proteins bind to Crk/CrkL Src homology 3 domains to activate host cell signaling. J. Biol. Chem. 2008, 283, 5719–5727. [Google Scholar] [CrossRef] [Green Version]
- Li, Z.; Jiang, Y.; Jiao, P.; Wang, A.; Zhao, F.; Tian, G.; Wang, X.; Yu, K.; Bu, Z.; Chen, H. The NS1 Gene Contributes to the Virulence of H5N1 Avian Influenza Viruses. J. Virol. 2006, 80, 11115–11123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, Q.; Yang, H.; Chen, W.; Cao, W.; Zhong, G.; Jiao, P.; Deng, G.; Yu, K.; Yang, C.; Bu, Z.; et al. A Naturally Occurring Deletion in Its NS Gene Contributes to the Attenuation of an H5N1 Swine Influenza Virus in Chickens. J. Virol. 2007, 82, 220–228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kochs, G.; Koerner, I.; Thiel, L.; Kothlow, S.; Kaspers, B.; Ruggli, N.; Summerfield, A.; Pavlovic, J.; Stech, J.; Staeheli, P. Properties of H7N7 influenza A virus strain SC35M lacking interferon antagonist NS1 in mice and chickens. J. Gen. Virol. 2007, 88, 1403–1409. [Google Scholar] [CrossRef] [PubMed]
- Solórzano, A.; Webby, R.J.; Lager, K.M.; Janke, B.H.; García-Sastre, A.; Richt, J.A. Mutations in the NS1 Protein of Swine Influenza Virus Impair Anti-Interferon Activity and Confer Attenuation in Pigs. J. Virol. 2005, 79, 7535–7543. [Google Scholar] [CrossRef] [Green Version]
- Long, J.-X.; Peng, D.-X.; Liu, Y.-L.; Wu, Y.-T.; Liu, X.-F. Virulence of H5N1 avian influenza virus enhanced by a 15-nucleotide deletion in the viral nonstructural gene. Virus Genes 2008, 36, 471–478. [Google Scholar] [CrossRef]
- Cho, E.J.; Xia, S.; Ma, L.-C.; Robertus, J.; Krug, R.M.; Anslyn, E.V.; Montelione, G.T.; Ellington, A.D. Identification of Influenza Virus Inhibitors Targeting NS1A Utilizing Fluorescence Polarization–Based High-Throughput Assay. J. Biomol. Screen. 2012, 17, 448–459. [Google Scholar] [CrossRef] [Green Version]
- You, L.; Cho, E.J.; Leavitt, J.; Ma, L.-C.; Montelione, G.T.; Anslyn, E.V.; Krug, R.M.; Ellington, A.; Robertus, J.D. Synthesis and evaluation of quinoxaline derivatives as potential influenza NS1A protein inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 3007–3011. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kleinpeter, A.B.; Jureka, A.S.; Falahat, S.M.; Green, T.J.; Petit, C.M. Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds. J. Biol. Chem. 2018, 293, 14659–14668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Walkiewicz, M.P.; Basu, D.; Jablonski, J.J.; Geysen, H.M.; Engel, D.A. Novel inhibitor of influenza non-structural protein 1 blocks multi-cycle replication in an RNase L-dependent manner. J. Gen. Virol. 2010, 92, 60–70. [Google Scholar] [CrossRef]
- Kile, J.C.; Ren, R.; Liu, L.; Greene, C.M.; Roguski, K.; Iuliano, A.D.; Jang, Y.; Jones, J.; Thor, S.; Song, Y.; et al. Update: Increase in Human Infections with Novel Asian Lineage Avian Influenza A(H7N9) Viruses During the Fifth Epidemic—China, October 1, 2016–August 7, 2017. MMWR Morb. Mortal. Wkly. Rep. 2017, 66, 928. [Google Scholar] [CrossRef] [Green Version]
- Ai, H.; Zhang, L.; Chang, A.K.; Wei, H.; Che, Y.; Liu, H. Virtual screening of potential inhibitors from TCM for the CPSF30 binding site on the NS1A protein of influenza A virus. J. Mol. Model. 2014, 20, 1–10. [Google Scholar] [CrossRef] [PubMed]
- Basu, D.; Walkiewicz, M.P.; Frieman, M.; Baric, R.S.; Auble, D.T.; Engel, D.A. Novel Influenza Virus NS1 Antagonists Block Replication and Restore Innate Immune Function. J. Virol. 2008, 83, 1881–1891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Patnaik, S.; Basu, D.; Southall, N.; Dehdashti, S.; Wan, K.K.; Zheng, W.; Ferrer, M.; Taylor, M.; Engel, D.A.; Marugan, J.J. Identification, design and synthesis of novel pyrazolopyridine influenza virus nonstructural protein 1 antagonists. Bioorganic Med. Chem. Lett. 2019, 29, 1113–1119. [Google Scholar] [CrossRef]
- Kuss-Duerkop, S.K.; Wang, J.; Mena, I.; White, K.; Metreveli, G.; Sakthivel, R.; Mata, M.A.; Muñoz-Moreno, R.; Chen, X.; Krammer, F.; et al. Influenza virus differentially activates mTORC1 and mTORC2 signaling to maximize late stage replication. PLoS Pathog. 2017, 13, e1006635. [Google Scholar] [CrossRef]
- Mata, M.A.; Satterly, N.; Versteeg, G.A.; Frantz, D.; Wei, S.; Williams, N.; Schmolke, M.; Peña-Llopis, S.; Brugarolas, J.; Forst, C.V.; et al. Chemical inhibition of RNA viruses reveals REDD1 as a host defense factor. Nat. Chem. Biol. 2011, 7, 712–719. [Google Scholar] [CrossRef] [Green Version]
- Nayak, M.K.; Agrawal, A.S.; Bose, S.; Naskar, S.; Bhowmick, R.; Chakrabarti, S.; Sarkar, S.; Chawla-Sarkar, M. Antiviral activity of baicalin against influenza virus H1N1-pdm09 is due to modulation of NS1-mediated cellular innate immune responses. J. Antimicrob. Chemother. 2014, 69, 1298–1310. [Google Scholar] [CrossRef] [Green Version]
- Wu, Y.; Zhang, G.; Li, Y.; Jin, Y.; Dale, R.; Sun, L.-Q.; Wang, M. Inhibition of highly pathogenic avian H5N1 influenza virus replication by RNA oligonucleotides targeting NS1 gene. Biochem. Biophys. Res. Commun. 2008, 365, 369–374. [Google Scholar] [CrossRef] [PubMed]
- Kumar, N.; Liang, Y.; Parslow, T.G.; Liang, Y.; Liang, Y. Receptor Tyrosine Kinase Inhibitors Block Multiple Steps of Influenza A Virus Replication. J. Virol. 2011, 85, 2818–2827. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, L.; Das, P.; Schmolke, M.; Manicassamy, B.; Wang, Y.; Deng, X.; Cai, L.; Tu, B.P.; Forst, C.V.; Roth, M.G.; et al. Inhibition of pyrimidine synthesis reverses viral virulence factor-mediated block of mRNA nuclear export. J. Cell Biol. 2012, 196, 315–326. [Google Scholar] [CrossRef] [PubMed]
Molecules | Targeting | Model Studied | Effects | Ref. |
---|---|---|---|---|
EGCG | NS1 | MDCK cells | Decreased the viral NS1 level and viral replication | [71] |
Quinoxaline | NS1 | MDCK cells | Inhibiting viral replication | [72] |
JJ3297 | NS1 | MEF cells | Reduced virus replication and produce level of IFN | [74] |
A22 | NS1 | NMR | Interrupt the NS1-CPSF30 binding | [75] |
Compound 32056, 31674 | NS1 | MM-PBSA | Binding with NS1 near the W187 | [76] |
NSC 109834, 128164, 95676, 125044 | NS1 | MDCK cells | Reduced viral M2 protein and RNAs | [77] |
pyrazolopyridine | NS1 | MDCK cells | Inhibition of virus replication | [78] |
Compound 3 | NS1 | MDCK cells | Decreased viral protein and replication | [79,80] |
Baicalin | NS1 | A549 cells | Reduced virus replication and viral NP transcription | [81] |
RNA oligonucleotide | NS1 | chicken embryo fibroblast cells | Interference to the viral transcription and replication | [82] |
AG879, tyrphostin A9 | Receptor tyrosine kinases | A549 cells | Inhibit the Crm1 nuclear export pathway and viral RNA synthesis | [83] |
Quinoline acid | dihydroorotate dehydrogenase | MDCK cells | Inhibition of production pyrimidines that limits virus replication | [84] |
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Kim, H.J.; Jeong, M.S.; Jang, S.B. Structure and Activities of the NS1 Influenza Protein and Progress in the Development of Small-Molecule Drugs. Int. J. Mol. Sci. 2021, 22, 4242. https://doi.org/10.3390/ijms22084242
Kim HJ, Jeong MS, Jang SB. Structure and Activities of the NS1 Influenza Protein and Progress in the Development of Small-Molecule Drugs. International Journal of Molecular Sciences. 2021; 22(8):4242. https://doi.org/10.3390/ijms22084242
Chicago/Turabian StyleKim, Hyeon Jin, Mi Suk Jeong, and Se Bok Jang. 2021. "Structure and Activities of the NS1 Influenza Protein and Progress in the Development of Small-Molecule Drugs" International Journal of Molecular Sciences 22, no. 8: 4242. https://doi.org/10.3390/ijms22084242