Viral M2 ion channel protein: A promising target for anti-influenza drug discovery

Mini-Reviews in Medicinal Chemistry

Volumn 14, Issue 10, 2014, Pages 819-830

  Hari Narayana Moorthy, N S ^a   Poongavanam, Vasanthanathan ^b   Pratheepa, V ^c  

^a UNIVERSITY OF PORTO   (Portugal)

^b UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^c UNIVERSITY OF PORTO   (Portugal)

Author keywords

Adamantane; Amantadine; Influenza virus; M2 proton channel; Neuraminidase; Rimantadine

Indexed keywords

AMANTADINE; AMIDE; ANTIVIRUS AGENT; FAVIPIRAVIR; FUNCTIONAL GROUP; HISTIDINE; HISTIDINE 37; ION CHANNEL; LANINAMIVIR; M2 PROTON CHANNEL; OSELTAMIVIR; PERAMIVIR; PROTEIN M2; PROTON PUMP; RIMANTADINE; UNCLASSIFIED DRUG; ZANAMIVIR; M2 PROTEIN, INFLUENZA A VIRUS; MATRIX PROTEIN;

ARTICLE; BINDING SITE; CHEMICAL INTERACTION; COMPUTER SIMULATION; DRUG STRUCTURE; HUMAN; HYDROGEN BOND; INFLUENZA; INFLUENZA VIRUS; INFLUENZA VIRUS A; INFLUENZA VIRUS B; MOLECULAR DYNAMICS; MOLECULAR MODEL; PH; PHASE 3 CLINICAL TRIAL (TOPIC); PROTEIN LOCALIZATION; PROTON TRANSPORT; STATIC ELECTRICITY; VIRUS MUTANT; VIRUS REPLICATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; INFLUENZA, HUMAN; METABOLISM; MOLECULARLY TARGETED THERAPY; ORTHOMYXOVIRIDAE; ORTHOMYXOVIRIDAE INFECTIONS; PHYSIOLOGY; VIROLOGY;

ANIMALS; ANTIVIRAL AGENTS; DRUG DISCOVERY; HUMANS; INFLUENZA A VIRUS; INFLUENZA, HUMAN; MODELS, MOLECULAR; MOLECULAR TARGETED THERAPY; ORTHOMYXOVIRIDAE; ORTHOMYXOVIRIDAE INFECTIONS; VIRAL MATRIX PROTEINS;

EID: 84911440795     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: None     Document Type: Article

References (85)

1. Pielak, R.M.; Chou. J.J. Influenza M2 proton channels. Biochim. Biophys. Acta, 2011, 1808(2), 522-529.
2. Stanicova, J.; Miskovsky, P.; Sutiak, V. Amantadine: an antiviral and antiparkinsonian agent. Vet. Med. Czech., 2001, 46(9–10), 244-256.
3. World Health Organization (2009) Influenza (Seasonal). Fact sheet No. 211, Available: http://www.who.int/mediacentre/factsheets/fs211/en/index.html. Accessed 11-09-2014.
4. Nicholls, H. Pandemic influenza: The Inside Story. PLoS Biol., 2006, 4, e50.
5. World Health Organization, Pandemic (H1N1) 2009 - update 75, Available: http://www.who.int/csr/don/2009_11_20a/en/index.html. Accessed 11-09-2014.
6. Viboud, C.; Simonsen, L. Global mortality of 2009 pandemic influenza A H1N1. Lancet Infect. Dis., 2012, 12(9), 651-653.
7. Balgi, A.; Wang, J.; Cheng, D.Y.H.; Ma, C.; Pfeifer, T.A.; Shimizu, Y.; Anderson, H.J.; Pinto, L.H.; Lamb, R.A.; DeGrado, W.F.; Roberge, M. Inhibitors of the influenza A virus M2 proton channel discovered using a high-throughput yeast growth restoration assay. PLoS ONE, 2013, 8(2), e55271.
8. Cheng, P.K.; To, A.P.; Leung, T.W.; Leung, P.C.; Lee, C.W.; Lim, W.W.L. Oseltamivir and amantadine-resistant influenza virus A (H1N1). Emerg. Infect. Dis., 2009, 16, 155-156.
9. Li, X.B.; Wang, S.Q.; Xu, W.R.; Wang, R.L.; Chou, K.C. Novel inhibitor design for hemagglutinin against H1N1 influenza virus by core hopping method. PLoS ONE, 2011, 6(11), e28111.
10. http://www.clintoncountypa.com/Pandemic%20Information/Influenzavirustypes.pdf, accessed on 11-09-2014.
11. http://www.vymedic.com/id56.html, accessed on 11-09-2014.
12. http://www.cdc.gov/flu/avianflu/influenza-a-virus-subtypes.html, accessed on 11-09-2014.
13. Bouvier, N.M.; Palese, P. The biology of influenza viruses. Vaccine, 2008, 26(Suppl 4), D49-D53.
14. Takeuchi, K.; Lamb, R.A. Influenza virus M2 protein ion channel activity stabilizes the native form of fowl plague virus hemagglutinin during intracellular transport. J. Virol., 1994, 68(2), 911-919.
15. Yang, J.; Li, M.; Shen, X.; Liu, S. Influenza A virus entry inhibitors targeting the hemagglutinin. Viruses, 2013, 5, 352-373.
16. Isaev, D.; Zhao, Q.; Kleen, J.K.; Lenck-Santini, P.P.; Adstamongkonkul, D.; Isaeva, E.; Holmes, G.L. Neuroaminidase reduces interictal spikes in a rat temporal lobe epilepsy model. Epilepsia, 2011, 52(3), e12-e15.
17. Harrod, M.E.; Emery, S.; Dwyer, D.E. Antivirals in the management of an influenza pandemic. Med. J. Aust., 2006, 185, S58-S61.
18. Edinger, T.O.; Pohl, M.O.; Stertz, S. Entry of influenza A virus: host factors and antiviral targets. J. Gen. Virol., 2014, 95, 263-277.
19. Pinto, L.H.; Lamb, R.A. Controlling influenza virus replication by inhibiting its proton channel. Mol. BioSyst., 2007, 3, 18-23.
20. Hay, A.J. The action of adamantanamines against influenza A viruses: inhibition of the M2 ion channel protein. Semin. Virol., 1992, 3, 21-30.
21. Lin, T.-I.; Schroeder, C. Definitive assignment of proton selectivity and attoampere unitary current to the M2 ion channel protein of influenza A virus. J. Virol., 2001, 75(8), 3647-3656.
22. Palese, P.; Shaw, M.L. In: Orthomyxoviridae: the viruses and their replication; Fields Virology; Knipe, D.M.; Howley, P.M. Ed. Lippincott, Williams & Wilkins: Philadelphia, 2007; pp. 1647-1689.
23. Adamson, A.L.; Chohan, K.; Swenson, J.; LaJeunesse, D. A Drosophila model for genetic analysis of influenza viral/host interactions. Genetics, 2011, 189, 495-506.
24. Du, J.; Cross, T.A.; Zhou, H.-X. Recent progress in structure-based anti-influenza drug design. Drug Discov. Today, 2012, 17(19/20), 1111-1120.
25. 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, 1306-1312.
26. Lin, T.I.; Heider, H.; Schroeder, C. Different modes of inhibition by adamantane amine derivatives and natural polyamines of the functionally reconstituted influenza virus M2 proton channel protein. J. Gen. Virol., 1997, 78: 767-774.
27. Pinto, L.H.; Lamb, R.A. Influenza virus proton channels. Photochem. Photobiol. Sci., 2006, 5, 629-632.
28. Pinto, L.H.; Lamb, R.A. The M2 proton channels of influenza A and B viruses. J. Biol. Chem., 2006, 281, 8997-9000.
29. Chang, T.T.; Sun, M.F.; Chen, H.Y.; Tsai, F.J.; Lin, J.G.; Chen, C.Y.C. Key features for designing M2 proton channel anti swine flu inhibitors. J. Taiwan Inst. Chem. Eng., 2011, 42, 701-708.
30. Pielak, R.M.; Schnell, J.R.; Chou, J.J. Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proc. Natl. Acad. Sci. USA, 2009, 106(18), 7379-7384.
31. Cegolon, L.; Salata, C.; Piccoli, E.; Juarez, V.; Palu, G.; Mastrangelo, G.; Calistri, A. In vitro antiviral activity of hypothiocyanite against A/H1N1/2009 pandemic influenza virus. Int. J. Hyg. Environ. Health, 2014, 217, 17-22.
32. Park, S., Kim, J., Lee, I., Lee, S., Hwang, M.W., Bae, J.Y., Heo, J., Kim, D., Jang, S., Kim, H., Cheong, H.J., Song, J.W., Song, K.W., Baek, L.J., Park, M.S. Combination effects of peramivir and favipiravir against oseltamivir-resistant 2009 pandemic influenza A(H1N1) infection in mice. PLoS ONE, 2014, 9(7), e101325.
33. http://www.isirv.org/site/index.php/clinical-trials. Accessed on 11-09-2014
34. Tarbet, E.B., Maekawa, M., Furuta, Y., Babu, Y.S., Morrey, J.D., Smee D.F. Combinations of favipiravir and peramivir for the treatment of pandemic influenza A/California/04/2009 (H1N1) virus infections in mice. Antiviral Res., 2012, 94(1), 103-110.
35. Ma, C.; Polishchuk, A.L.; Ohigashi, Y.; Stouffer, A.L.; Schon, A.; Magavern, E.; Jing, X.; Lear, J.D.; Freire, E.; Lamb, R.A.; DeGrado, W.F.; Pinto, L.H. Identification of the functional core of the influenza A virus A/M2 proton-selective ion channel. Proc. Natl. Acad. Sci. USA, 2009, 106(30), 12283-12288.
36. Hay, A.J.; Wolstenholme, A.J.; Skehel, J.J.; Smith, M.H. The molecular basis of the specific anti-influenza action of amantadine. EMBO J., 1985, 4, 3021-3024.
37. Duque, M.D.; Torres, E.; Valverde, E.; Barniol, M.; Guardiola, S.; Rey, M.; Vázquez, S. 2. Inhibitors of the M2 channel of influenza A virus. Recent Adv. Pharmaceut. Sci., 2011, 35-64.
38. Rogers, J.M.G.; Polishchuk, A.L.; Guo, L.; Wang, J.; DeGrado, W.F.; Gai, F. Photo induced electron transfer and fluorophore motion as a probe of the conformational dynamics of membrane proteins: application to the influenza a M2 proton channel. Langmuir, 2011, 27, 3815-3821.
39. Laohpongspaisan, C.; Rungrotmongkol, T.; Intharathep, P.; Malaisree, M.; Decha, P.; Aruksakunwong, O.; Sompornpisut, P.; Hannongbua, S. Why amantadine loses its function in influenza M2 mutants: MD simulations. J. Chem. Inf. Model., 2009, 49, 847-852.
40. Qin, G.; Yu, K.; Shi, T.; Luo, C.; Li, G.; Zhu, W.; Jiang, H. How does influenza virus an escape from amantadine? J. Phys. Chem. B, 2010, 114, 8487-8493.
41. Betakova, T. M2 protein-a proton channel of influenza A virus. Curr. Pharm. Des., 2007, 13, 3231-3235.
42. Das, K.; Aramini, J.M.; Ma, L.C.; Krug, R.M.; Arnold, E. Structures of influenza A proteins and insights into antiviral drug targets. Nat. Struct. Mol. Biol., 2010, 17(5), 530-538.
43. Alhadeff, R.; Assa, D.; Astrahan, P.; Krugliak, M.; Arkin, I.T. Computational and experimental analysis of drug binding to the influenza M2 channel. Biochim. Biophy. Acta., 2014, 1838(4), 1068-1073
44. Deyde, V.M.; Xu, X.; Bright, R.A.; Shaw, M.; Smith, C.B.; Zhang, Y.; Shu, Y.; Gubareva, L.V.; Cox, N.J.; Klimov, A.I. Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J. Infect. Dis., 2007, 196, 249-257.
45. Bright, R.A.; Shay, D.K.; Shu, B.; Cox, N.J.; Klimov, A.I. Adamantane resistance among influenza A viruses isolated early during the 2005–2006 influenza season in the United States. J. Am. Med. Assoc., 2006, 295, 891-894.
46. Bright, R.A.; Medina, M.J.; Xu, X.; Perez-Oronoz, G.; Wallis, T.R.; Davis, X.M.; Povinelli, L.; Cox, N.J.; Klimov, A.I. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet, 2005, 366, 1175-1181.
47. Wang, J.; Ma, C.; Fiorin, G.; Carnevale, V.; Wang, T.; Hu, F.; Lamb, R.A.; Pinto, L.H.; Hong, M.; Klein, M.L.; DeGrado, W.F. Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2. J. Am. Chem. Soc., 2011, 133, 12834-12841.
48. Furuse, Y.; Suzuki, A.; Oshitani, H. Large-scale sequence analysis of M gene of influenza A viruses from different species: mechanisms for emergence and spread of amantadine resistance. Antimicrob. Agents Chemother., 2009, 53, 4457-4463.
49. Wang, J.; Wu, Y.; Ma, C.; Fiorin, G.; Wang, J.; Pinto, L.H.; Lamb, R.A.; Klein, M.L.; DeGrado, W.F. Structure and inhibition of the drug-resistant S31N mutant of the M2 ion channel of influenza A virus. Proc. Natl. Acad. Sci. USA, 2013, 110(4), 1315-1320.
50. Monto, A.S. The role of antivirals in the control of influenza. Vaccine, 2003, 21, 1796-1800.
51. Duque, M.D.; Ma, C.; Torres, E.; Wang, J.; Naesens, L.; Juarez-Jimenez, J.; Camps, P.; Luque, F.J.; DeGrado, W.F.; Lamb, R.A.; Pinto, L.H.; Vazquez, S. Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus. J. Med. Chem., 2011, 54, 2646-2657.
52. Cady, S.D.; Wang, J.; Wu, Y.; DeGrado, W.F.; Hong, M. Specific binding of adamantane drugs and direction of their polar amines in the pore of the influenza M2 transmembrane domain in lipid bilayers and dodecylphosphocholine micelles determined by NMR spectroscopy. J. Am. Chem. Soc., 2011, 133, 4274-4284.
53. Hu, J.; Asbury, T.; Achuthan, S.; Li, C.; Bertram, R.; Quine, J.R.; Fu, R.; Cross, T.A. Backbone structure of the amantadine-blocked trans-membrane domain M2 proton channel from influenza A virus. Biophy. J., 2007, 92, 4335-4343.
54. Kurtz, S.; Luo, G.X.; Hahnenberger, K.M.; Brooks, C.; Gecha, O.; Ingalls, K.; Numata, K.I.; Krystal, M. Growth impairment resulting from expression of influenza virus M2 protein in Saccharomyces cerevisiae: identification of a novel inhibitor of influenza virus. Antimicrob. Agents Chemother., 1995, 39, 2204-2209.
55. Cady, S.D.; Luo, W.; Hu, F.; Hong, M. Structure and function of the influenza A M2 proton channel. Biochemistry, 2009, 48, 7356-7364.
56. Tu, Q.; Pinto, L.H.; Luo, G.; Shaughnessy, M.A.; Mullaney, D.; Kurtz, S.; Krystal, M.; Lamb, R.A. Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus. J. Virol., 1996, 70, 4246-4252.
57. Wang, J.; Cady, S.D.; Balannik, V.; Pinto, L.H.; DeGrado, W.F.; Hong, M. Discovery of spiro-piperidine inhibitors and their modulation of the dynamics of the M2 proton channel from influenza A virus. J. Am. Chem. Soc., 2009, 131, 8066-8076.
58. Zhao, X.; Jie, Y.; Rosenberg, M.R.; Wan, J.; Zeng, S.; Cui, W.; Xiao, Y.; Li, Z.; Tu, Z.; Casarotto, M.G.; Hu, W. Design and synthesis of pinanamine derivatives as anti-influenza A M2 ion channel inhibitors. Antiviral Res., 2012, 96, 91-99.
59. DeGrade, W.F.; Wang, J. Inhibitors of the influenza A virus M2 proton channel. U.S. Patent 00,28,957A1, February 2, 2012.
60. DeGrado, W.F.; Wang, J. Inhibitors of the influenza A virus M2 proton channel. U.S. Patent 85,69,284B2, October 29, 2013.
61. DeGrado, W.F.; Wang J. Inhibition of influenza A M2 proton channel. U.S. Patent 02,88,111A1, November 24, 2011.
62. DeGrado, W.F.; Wang, J. Inhibition of influenza M2 proton channel. World Organization Patent 03,339A1, March 25, 2010.
63. DeGrado, W.F.; Wang, J. Inhibitors of the influenza A virus M2 proton channel. U.S. Patent 00,28,957A1, February 2, 2012.
64. DeGrado, W.F.; Wang, J. Influenza A virus inhibition. U.S. Patent 02,94,785A1, December 1, 2011.
65. Du, Q.-S.; Huang, R.-B.; Wang, S.-Q.; Chou, K.-C. Designing inhibitors of M2 proton channel against H1N1 Swine influenza virus. PLoS ONE, 2010, 5(2), e9388.
66. Sansom, M.S.; Kerr, I.D. Influenza virus M2 protein: a molecular modelling study of the ion channel. Protein Eng., 1993, 6, 65-74.
67. Pielak, R.M.; Chou, J.J. Flu channel drug resistance: a tale of two sites. Protein Cell, 2010, 1(3), 246-258.
68. Yi, M.; Cross, T.A.; Zhou, H.-X. A secondary gate as a mechanism for inhibition of the M2 proton channel by amantadine. J. Phys. Chem. B, 2008, 112(27), 7977-7979.
69. Tambunan, U.S.F.; Rahdiansyah, M.R.; Parikesit, A.A. In silico design of the M2 proton channel inhibitors of H1N1 virus. OnLine J. Biol. Sci., 2013, 13(1), 1-12.
70. Balannik, V.; Wang, J.; Ohigashi, Y.; Jing, X.; Magavern, E.; Lamb, R.A.; DeGrado, W.F.; Pinto, L.H. Design and pharmacological characterization of inhibitors of amantadineresistant mutants of the M2 ion channel of influenza A virus. Biochemistry, 2009, 48, 11872-11882.
71. Leonov, H.; Astrahan, P.; Krugliak, M.; Arkin, I.T. How do aminoadamantanes block the influenza M2 channel, and how does resistance develop?. J. Am. Chem. Soc., 2011, 133, 9903-9911.
72. Eleftheratos, S.; Spearpoint, P.; Ortore, G.; Kolocouris, A.; Martinelli, A.; Martin, S.; Hay, A. Interaction of aminoadamantane derivatives with the influenza A virus M2 channel-Docking using a pore blocking model. Bioorg. Med. Chem. Lett., 2010, 20, 4182-4187.
73. Mould, J.A.; Drury, J.E.; Frings, S.M.; Kaupp, U.B.; Pekosz, A.; Lamb, R.A.; Pinto, L.H. Permeation and activation of the M2 ion channel of influenza A virus. J. Biol. Chem., 2000, 275(40), 31038-31050.
74. De Azevedo, W.F. Jr, Dias, R. Computational methods for calculation of ligand-binding affinity. Curr. Drug Targets, 2008, 9(12), 1031-1039.
75. Gadelha, C.A.; Moreno, F.B.; Santi-Gadelha, T.; Cajazeiras, J.B.; Rocha, B.A.; Assreuy, A.M.; Lima Mota, M.R.; Pinto, N.V.; Passos Meireles, A.V.; Borges, J.C.; Freitas, B.T.; Canduri, F.; Souza, E.P.; Delatorre, P.; Criddle, D.N.; de Azevedo, W.F. Jr, Cavada, B.S. Native crystal structure of a nitric oxide-releasing lectin from the seeds of Canavalia maritima. J. Struct. Biol., 2005, 152(3), 185-194.
76. dos Santos Cabrera, M.P.; de Souza, B.M.; Fontana, R.; Konno, K.; Palma, M.S.; de Azevedo, W.F. Jr, Neto, J.R. Conformation and lytic activity of Eumenine mastoparan: a new antimicrobial peptide from wasp venom. J. Pept. Res., 2004, 64(3), 95-103.
77. Fadel, V.; Bettendorff, P.; Herrmann, T.; de Azevedo, W.F. Jr, Oliveira, E.B.; Yamane, T.; Wüthrich, K. Automated NMR structure determination and disulfide bond identification of the myotoxin crotamine from Crotalus durissus terrificus. Toxicon, 2005, 46(7), 759-767.
78. Wang, J.; Ma, C.; Balannik, V.; Pinto, L.H.; Lamb, R.A.; DeGrado, W.F. Exploring the requirements for the hydrophobic scaffold and polar amine in inhibitors of M2 from influenza A virus. ACS Med. Chem. Lett., 2011, 2:, 307-312.
79. Baz, M.; Abed, Y.; Papenburg, J.; Bouhy, X.; Hamelin, M.A.; Boivin, G.N. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. Engl. J. Med., 2009, 361, 2296-2297.
80. Wang, J.; Ma, C.; Wu, Y.; Lamb, R.A.; Pinto, L.H.; DeGrado, W.F. Exploring organosilane amines as potent inhibitors and structural probes of influenza A virus M2 proton channel. J. Am. Chem. Soc., 2011, 133, 13844-13877.
81. Hayden, F.G.; Minocha, A.; Spyker, D.A.; Hoffman, H.E. Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults. Antimicrob. Agents Chemother., 1985, 28, 216-221.
82. Gu, R.-X.; Liu, L.A.; Wang, Y.-H.; Xu, Q.; Wei, D.-Q. Structural comparison of the wild-type and drug-resistant mutants of the influenza A M2 proton channel by molecular dynamics simulations. J. Phys. Chem. B, 2013, 117, 6042-6051.
83. Schnell, J.R.; Chou, J.J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature, 2008, 451, 591-596.
84. Wang, C.; Takeuchi, K.; Pinto, L.H.; Lamb, R.A. Ion channel activity of influenza A virus M2 protein: Characterization of the amantadine block. J. Virol., 1993, 67, 5585-5594.
85. Stouffer, A.L.; Nanda, V.; Lear, J.D.; DeGrado, W.F. Sequence determinants of a transmembrane proton channel: an inverse relationship between stability and function. J. Mol. Biol., 2005, 347, 169-179.