1887

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Volume 91, Issue 11

-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity Free

Abstract

Based on the structural similarity of viral fusion proteins within the family , we tested recently described and newly synthesized acetanilide derivatives for their capacity to inhibit measles virus (MV)-, canine distemper virus (CDV)- and Nipah virus (NiV)-induced membrane fusion. We found that -(3-cyanophenyl)-2-phenylacetamide (compound 1) has a high capacity to inhibit MV- and CDV-induced (IC=3 μM), but not NiV-induced, membrane fusion. This compound is of outstanding interest because it can be easily synthesized and its cytotoxicity is low [50 % cytotoxic concentration (CC)≥300 μM], leading to a CC/IC ratio of approximately 100. In addition, primary human peripheral blood lymphocytes and primary dog brain cell cultures (DBC) also tolerate high concentrations of compound 1. Infection of human PBMC with recombinant wild-type MV is inhibited by an IC of approximately 20 μM. The cell-to-cell spread of recombinant wild-type CDV in persistently infected DBC can be nearly completely inhibited by compound 1 at 50 μM, indicating that the virus spread between brain cells is dependent on the activity of the viral fusion protein. Our findings demonstrate that this compound is a most applicable inhibitor of morbillivirus-induced membrane fusion in tissue culture experiments including highly sensitive primary cells.

  • Received:
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2010-11-01
2024-04-23
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References

  1. Appel, M. J. G., Gillespie, J. H. & Siegert, R.(1972). Canine distemper virus. Virol Monogr 11, 1–96. [Google Scholar]
  2. Blixenkrone-Moller, M., Svansson, V., Have, P., Orvell, C., Appel, M., Pedersen, I. R., Dietz, H. H. & Henriksen, P.(1993). Studies on manifestations of canine distemper virus infection in an urban dog population. Vet Microbiol 37, 163–173.[CrossRef] [Google Scholar]
  3. Butler, D.(2004). Fatal fruit bat virus sparks epidemics in southern Asia. Nature 429, 7. [Google Scholar]
  4. Chadha, M. S., Comer, J. A., Lowe, L., Rota, P. A., Rollin, P. E., Bellini, W. J., Ksiazek, T. G. & Mishra, A.(2006). Nipah virus-associated encephalitis outbreak, Siliguri, India. Emerg Infect Dis 12, 235–240.[CrossRef] [Google Scholar]
  5. Chong, H. T., Kamarulzaman, A., Tan, C. T., Goh, K. J., Thayaparan, T., Kunjapan, S. R., Chew, N. K., Chua, K. B. & Lam, S. K.(2001). Treatment of acute Nipah encephalitis with ribavirin. Ann Neurol 49, 810–813.[CrossRef] [Google Scholar]
  6. Chua, K. B.(2003). Nipah virus outbreak in Malaysia. J Clin Virol 26, 265–275.[CrossRef] [Google Scholar]
  7. Condack, C., Grivel, J. C., Devaux, P., Margolis, L. & Cattaneo, R.(2007). Measles virus vaccine attenuation: suboptimal infection of lymphatic tissue and tropism alteration. J Infect Dis 196, 541–549.[CrossRef] [Google Scholar]
  8. De Franceschi, L., Fattovich, G., Turrini, F., Ayi, K., Brugnara, C., Manzato, F., Noventa, F., Stanzial, A. M., Solero, P. & Corrocher, R.(2000). Hemolytic anemia induced by ribavirin therapy in patients with chronic hepatitis C virus infection: role of membrane oxidative damage. Hepatology 31, 997–1004.[CrossRef] [Google Scholar]
  9. de Swart, R. L., Ludlow, M., de Witte, L., Yanagi, Y., van Amerongen, G., McQuaid, S., Yuksel, S., Geijtenbeek, T. B., Duprex, W. P. & Osterhaus, A. D.(2007). Predominant infection of CD150+ lymphocytes and dendritic cells during measles virus infection of macaques. PLoS Pathog 3, e178.[CrossRef] [Google Scholar]
  10. Dittmar, S., Harms, H., Runkler, N., Maisner, A., Kim, K. S. & Schneider-Schaulies, J.(2008). Measles virus-induced block of transendothelial migration of T lymphocytes and infection-mediated virus spread across endothelial cell barriers. J Virol 82, 11273–11282.[CrossRef] [Google Scholar]
  11. Doyle, J., Prussia, A., White, L. K., Sun, A., Liotta, D. C., Snyder, J. P., Compans, R. W. & Plemper, R. K.(2006). Two domains that control prefusion stability and transport competence of the measles virus fusion protein. J Virol 80, 1524–1536.[CrossRef] [Google Scholar]
  12. Duclos, P. & Ward, B. J.(1998). Measles vaccines: a review of adverse events. Drug Saf 19, 435–454.[CrossRef] [Google Scholar]
  13. Elia, G., Belloli, C., Cirone, F., Lucente, M. S., Caruso, M., Martella, V., Decaro, N., Buonavoglia, C. & Ormas, P.(2008).In vitro efficacy of ribavirin against canine distemper virus. Antiviral Res 77, 108–113.[CrossRef] [Google Scholar]
  14. Epand, R. M.(1986). Virus replication inhibitory peptide inhibits the conversion of phospholipid bilayers to the hexagonal phase. Biosci Rep 6, 647–653.[CrossRef] [Google Scholar]
  15. Erlenhoefer, C., Wurzer, W. J., Löffler, S., Schneider-Schaulies, S., ter Meulen, V. & Schneider-Schaulies, J.(2001). CD150 (SLAM) is a receptor for measles virus, but is not involved in viral contact-mediated proliferation inhibition. J Virol 75, 4499–4505.[CrossRef] [Google Scholar]
  16. Erlenhoefer, C., Duprex, W. P., Rima, B. K., ter Meulen, V. & Schneider-Schaulies, J.(2002). Analysis of receptor (CD46, CD150) usage by measles virus. J Gen Virol 83, 1431–1436. [Google Scholar]
  17. Ferreira, C. S., Frenzke, M., Leonard, V. H., Welstead, G. G., Richardson, C. D. & Cattaneo, R.(2010). Measles virus infection of alveolar macrophages and dendritic cells precedes spread to lymphatic organs in transgenic mice expressing human signaling lymphocytic activation molecule (SLAM, CD150). J Virol 84, 3033–3042.[CrossRef] [Google Scholar]
  18. Gemma, T., Watari, T., Akiyama, K., Miyashita, N., Shin, Y. S., Iwatsuki, K., Kai, C. & Mikami, T.(1996). Epidemiological observations on recent outbreaks of canine distemper in Tokyo area. J Vet Med Sci 58, 547–550.[CrossRef] [Google Scholar]
  19. Georges-Courbot, M. C., Contamin, H., Faure, C., Loth, P., Baize, S., Leyssen, P., Neyts, J. & Deubel, V.(2006). Poly(I)-poly(C12U) but not ribavirin prevents death in a hamster model of Nipah virus infection. Antimicrob Agents Chemother 50, 1768–1772.[CrossRef] [Google Scholar]
  20. Graci, J. D. & Cameron, C. E.(2006). Mechanisms of action of ribavirin against distinct viruses. Rev Med Virol 16, 37–48.[CrossRef] [Google Scholar]
  21. Gururangan, S., Stevens, R. F. & Morris, D. J.(1990). Ribavirin response in measles pneumonia. J Infect 20, 219–221.[CrossRef] [Google Scholar]
  22. Harder, T. C. & Osterhaus, A. D.(1997). Canine distemper virus – a morbillivirus in search of new hosts? Trends Microbiol 5, 120–124.[CrossRef] [Google Scholar]
  23. Hashimoto, K., Ono, N., Tatsuo, H., Minagawa, H., Takeda, M., Takeuchi, K. & Yanagi, Y.(2002). SLAM (CD150)-independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein. J Virol 76, 6743–6749.[CrossRef] [Google Scholar]
  24. Honda, Y., Hosoya, M., Ishii, T., Shigeta, S. & Suzuki, H.(1994). Effect of ribavirin on subacute sclerosing panencephalitis virus infections in hamsters. Antimicrob Agents Chemother 38, 653–655.[CrossRef] [Google Scholar]
  25. Huffman, J. H., Sidwell, R. W., Khare, G. P., Witkowski, J. T., Allen, L. B. & Robins, R. K.(1973).In vitro effect of 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide (virazole, ICN 1229) on deoxyribonucleic acid and ribonucleic acid viruses. Antimicrob Agents Chemother 3, 235–241.[CrossRef] [Google Scholar]
  26. Ishii, T., Hosoya, M., Mori, S., Shigeta, S. & Suzuki, H.(1996). Effective ribavirin concentration in hamster brains for antiviral chemotherapy for subacute sclerosing panencephalitis. Antimicrob Agents Chemother 40, 241–243. [Google Scholar]
  27. Ludlow, M., Allen, I. & Schneider-Schaulies, J.(2009). Systemic spread of measles virus: overcoming the epithelial and endothelial barriers. Thromb Haemost 102, 1050–1056. [Google Scholar]
  28. Meanwell, N. A. & Krystal, M.(2000). Respiratory syncytial virus: recent progress towards the discovery of effective prophylactic and therapeutic agents. Drug Discov Today 5, 241–252. [Google Scholar]
  29. Meanwell, N. A. & Krystal, M.(2000). Respiratory syncytial virus: recent progress towards the discovery of effective prophylactic and therapeutic agents. Drug Discov Today 5, 241–252. [Google Scholar]
  30. Moll, M., Pfeuffer, J., Klenk, H.-D., Niewiesk, S. & Maisner, A.(2004). Polarized glycoprotein targeting affects the spread of measles virus in vitro and in vivo. J Gen Virol 85, 1019–1027.[CrossRef] [Google Scholar]
  31. Murray, K., Selleck, P., Hooper, P., Hyatt, A., Gould, A., Gleeson, L., Westbury, H., Hiley, L., Selvey, L. & other authors(1995). A morbillivirus that caused fatal disease in horses and humans. Science 268, 94–97.[CrossRef] [Google Scholar]
  32. Nanan, R., Chittka, B., Hadam, M. & Kreth, H. W.(1999). Measles virus infection causes transient depletion of activated T cells from peripheral circulation. J Clin Virol 12, 201–210.[CrossRef] [Google Scholar]
  33. Negrete, O. A., Levroney, E. L., Aguilar, H. C., Bertolotti-Ciarlet, A., Nazarian, R., Tajyar, S. & Lee, B.(2005). EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature 436, 401–405. [Google Scholar]
  34. Niedermeier, S., Singethan, K., Rohrer, S. G., Matz, M., Kossner, M., Diederich, S., Maisner, A., Schmitz, J., Hiltensperger, G. & other authors(2009). A small-molecule inhibitor of Nipah virus envelope protein-mediated membrane fusion. J Med Chem 52, 4257–4265.[CrossRef] [Google Scholar]
  35. Pfeuffer, J., Püschel, K., ter Meulen, V., Schneider-Schaulies, J. & Niewiesk, S.(2003). Extent of measles virus spread and immune suppression differentiates between wild-type and vaccine strains in the cotton rat model (Sigmodon hispidus). J Virol 77, 150–158.[CrossRef] [Google Scholar]
  36. Plattet, P., Zweifel, C., Wiederkehr, C., Belloy, L., Cherpillod, P., Zurbriggen, A. & Wittek, R.(2004). Recovery of a persistent canine distemper virus expressing the enhanced green fluorescent protein from cloned cDNA. Virus Res 101, 147–153.[CrossRef] [Google Scholar]
  37. Plattet, P., Rivals, J. P., Zuber, B., Brunner, J. M., Zurbriggen, A. & Wittek, R.(2005). The fusion protein of wild-type canine distemper virus is a major determinant of persistent infection. Virology 337, 312–326.[CrossRef] [Google Scholar]
  38. Plattet, P., Langedijk, J. P., Zipperle, L., Vandevelde, M., Orvell, C. & Zurbriggen, A.(2009). Conserved leucine residue in the head region of morbillivirus fusion protein regulates the large conformational change during fusion activity. Biochemistry 48, 9112–9121.[CrossRef] [Google Scholar]
  39. Plemper, R. K., Erlandson, K. J., Lakdawala, A. S., Sun, A., Prussia, A., Boonsombat, J., Aki-Sener, E., Yalcin, I., Yildiz, I. & other authors(2004). A target site for template-based design of measles virus entry inhibitors. Proc Natl Acad Sci U S A 101, 5628–5633.[CrossRef] [Google Scholar]
  40. Plemper, R. K., Doyle, J., Sun, A., Prussia, A., Cheng, L. T., Rota, P. A., Liotta, D. C., Snyder, J. P. & Compans, R. W.(2005). Design of a small-molecule entry inhibitor with activity against primary measles virus strains. Antimicrob Agents Chemother 49, 3755–3761.[CrossRef] [Google Scholar]
  41. Richardson, C. D. & Choppin, P. W.(1983). Oligopeptides that specifically inhibit membrane fusion by paramyxoviruses: studies on the site of action. Virology 131, 518–532.[CrossRef] [Google Scholar]
  42. Schneider-Schaulies, S. & Schneider-Schaulies, J.(2009). Measles virus-induced immunosuppression. Curr Top Microbiol Immunol 330, 243–269. [Google Scholar]
  43. Summers, B. A. & Appel, M. J. G.(1994). Aspects of canine distemper virus and measles virus encephalomyelitis. Neuropathol Appl Neurobiol 20, 525–534.[CrossRef] [Google Scholar]
  44. Sun, A., Prussia, A., Zhan, W., Murray, E. E., Doyle, J., Cheng, L. T., Yoon, J. J., Radchenko, E. V., Palyulin, V. A. & other authors(2006). Nonpeptide inhibitors of measles virus entry. J Med Chem 49, 5080–5092.[CrossRef] [Google Scholar]
  45. Tan, C. T., Goh, K. J., Wong, K. T., Sarji, S. A., Chua, K. B., Chew, N. K., Murugasu, P., Loh, Y. L., Chong, H. T. & other authors(2002). Relapsed and late-onset Nipah encephalitis. Ann Neurol 51, 703–708.[CrossRef] [Google Scholar]
  46. Tatsuo, H., Ono, N., Tanaka, K. & Yanagi, Y.(2000). SLAM (CDw150) is a cellular receptor for measles virus. Nature 406, 893–897.[CrossRef] [Google Scholar]
  47. Vandevelde, M. & Zurbriggen, A.(1995). The neurobiology of canine distemper virus infection. Vet Microbiol 44, 271–280.[CrossRef] [Google Scholar]
  48. Vandevelde, M. & Zurbriggen, A.(2005). Demyelination in canine distemper virus infection: a review. Acta Neuropathol 109, 56–68.[CrossRef] [Google Scholar]
  49. von Messling, V., Springfeld, C., Devaux, P. & Cattaneo, R.(2003). A ferret model of canine distemper virus virulence and immunosuppression. J Virol 77, 12579–12591.[CrossRef] [Google Scholar]
  50. Weissbrich, B., Schneider-Schaulies, J. & ter Meulen, V.(2003).Measles and its neurological complications. Edited by Nath, A. & Berger, J. R.. New York. : Marcel Dekker. [Google Scholar]
  51. Wong, K. T., Shieh, W. J., Kumar, S., Norain, K., Abdullah, W., Guarner, J., Goldsmith, C. S., Chua, K. B., Lam, S. K. & other authors(2002). Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 161, 2153–2167.[CrossRef] [Google Scholar]
  52. Wyss-Fluehmann, G., Zurbriggen, A., Vandevelde, M. & Plattet, P.(2010). Canine distemper virus persistence in demyelinating encephalitis by swift intracellular cell-to-cell spread in astrocytes is controlled by the viral attachment protein. Acta Neuropathol 119, 617–630.[CrossRef] [Google Scholar]
  53. Zurbriggen, A., Vandevelde, M., Beranek, C. F. & Steck, A.(1984). Morphological and immunocytochemical characterisation of mixed glial cell cultures derived from neonatal canine brain. Res Vet Sci 36, 270–275. [Google Scholar]
  54. Zurbriggen, A., Graber, H. U., Wagner, A. & Vandevelde, M.(1995). Canine distemper virus persistence in the nervous system is associated with noncytolytic selective virus spread. J Virol 69, 1678–1686. [Google Scholar]
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N-(3-Cyanophenyl)-2-phenylacetamide, an effective inhibitor of morbillivirus-induced membrane fusion with low cytotoxicity
J. Gen. Virol. 91, 2762 (2010); https://doi.org/10.1099/vir.0.025650-0
/content/journal/jgv/10.1099/vir.0.025650-0
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