Skip to main content
SpringerLink
Log in

Inhibitors of Protein-Protein Interactions in Paramyxovirus Fusion: A Focus on Respiratory Syncytial Virus

  • Chapter
  • First Online:
Protein-Protein Interactions

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 8))

Abstract

The assembly of the N-terminus heptad repeats of the respiratory syncytial virus (RSV) F protein into a trimeric complex that associates with the C-terminus heptad repeats to form a six-helix bundle is a critical step in the process of virus-host fusion and represents an intramolecular protein-protein interaction. Screening campaigns using replicating virus assays have identified several structurally distinct but mechanistically similar chemotypes that interfere with RSV fusion by disrupting the function of the F protein six-helix bundle. This chapter summarizes structure-activity relationships and mechanistic insights associated with the most prominent RSV fusion inhibitors and the key issues in the development of potential clinical candidates.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Eckert DM, Kim PS (2001) Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem 70:777–810

    CAS  Google Scholar 

  2. Peisajovich SG, Shai Y (2002) New insights into the mechanism of virus-induced membrane fusion. Trends Biochem Sci 27:183–190

    CAS  Google Scholar 

  3. Colman PM, Lawrence MC (2003) The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol 4:309–319

    CAS  Google Scholar 

  4. Smith AE, Helenius A (2004) How viruses enter animal cells. Science 304:237–242

    CAS  Google Scholar 

  5. Earp LJ, Delos SE, Park HE, White JM (2005) The many mechanisms of viral membrane fusion proteins. Curr Top Microbiol Immunol 285:25–66

    CAS  Google Scholar 

  6. Lamb RA, Jardetzky TS (2007) Structural basis of viral invasion: lessons from paramyxovirus F. Curr Opin Struct Biol 17:427–436

    CAS  Google Scholar 

  7. Harrison SC (2008) Viral membrane fusion. Nat Struct Mol Biol 15:690–698

    CAS  Google Scholar 

  8. Zhao X, Singh M, Malashkevich VN, Kim PS (2000) Structural characterization of the human respiratory syncytial virus fusion protein core. Proc Natl Acad Sci USA 97:14172–14177

    CAS  Google Scholar 

  9. Chan DC, Chutkowski CT, Kim PS (1998) Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target. Proc Natl Acad Sci USA 95:15613–15617

    CAS  Google Scholar 

  10. Debnath AK (2006) Prospects and strategies for the discovery and development of small-molecule inhibitors of six-helix bundle formation in class 1 viral fusion proteins. Curr Opin Investig Drugs 7:118–127

    CAS  Google Scholar 

  11. Wild C, Oas T, McDanal C et al (1992) A synthetic peptide inhibitor of human immunodeficiency virus replication: correlation between solution structure and viral inhibition. Proc Natl Acad Sci USA 89:10537–10541

    CAS  Google Scholar 

  12. Wild C, Greenwell T, Shugars D et al (1995) The inhibitory activity of an HIV type 1 peptide correlates with its ability to interact with a leucine zipper structure. AIDS Res Hum Retrovir 11:323–325

    CAS  Google Scholar 

  13. Lu M, Blacklow SC, Kim PS (1995) A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat Struct Biol 2:1075–1082

    CAS  Google Scholar 

  14. Chan DC, Fass D, Berger JM, Kim PS (1997) Core structure of gp41 from the HIV envelope glycoprotein. Cell 89:263–273

    CAS  Google Scholar 

  15. Del Vecchio AM, Sarisky RT (2006) Cold virus fusion or stopping fusion cold – inhibitors of the human respiratory syncytial virus F protein. Recent Pat AntiInfect Drug Discov 1:247–254

    Google Scholar 

  16. Meanwell NA, Krystal M (2007) Respiratory syncytial virus – the discovery and optimization of orally bioavailable fusion inhibitors. Drugs Future 32:441–455

    CAS  Google Scholar 

  17. Carter M, Cockerill GS (2008) Inhibitors of respiratory syncytial virus. Annu Rep Med Chem 43:229–245

    CAS  Google Scholar 

  18. Bonfanti J-F, Roymans D (2009) Prospects for the development of fusion inhibitors to treat human respiratory syncytial virus infection. Curr Opin Drug Discov Dev 12:479–487

    CAS  Google Scholar 

  19. Olszewska W, Openshaw P (2009) Emerging drugs for respiratory syncytial virus infection. Exp Opin Emerg Drugs 14:207–217

    CAS  Google Scholar 

  20. Murineddu G, Murruzzu C, Pinna GA (2010) An overview on different classes of viral entry and respiratory syncytial virus (RSV) fusion inhibitors. Curr Med Chem 17:1067–1091

    CAS  Google Scholar 

  21. Collins PL, McIntosh K, Chanock RM (2002) Respiratory syncytial virus. In: Knipe DM, Howley PM (eds) Fields virology. Raven, New York

    Google Scholar 

  22. Blount RE Jr, Morris JA, Savage RE (1956) Recovery of cytopathogenic agent from chimpanzees with coryza. Proc Soc Exp Biol Med 92:544–549

    Google Scholar 

  23. Chanock R, Roizman B, Myers R (1957) Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). I. Isolation, properties and characterization. Am J Hyg 66:281–290

    CAS  Google Scholar 

  24. Chanock R, Finberg L (1957) Recovery from infants with respiratory illness of a virus related to chimpanzee coryza agent (CCA). II. Epidemiologic aspects of infection in infants and young children. Am J Hyg 66:291–300

    CAS  Google Scholar 

  25. Rowe DS, Michaels RH (1960) Isolation of the respiratory syncytial virus from a patient with pneumonia. Pediatrics 6:623–629

    Google Scholar 

  26. Tang Y-W, Crowe JE Jr (2007) Respiratory syncytial virus and human metapneumovirus. In: Murray PR (ed) Manual of clinical microbiology, 9th edn. ASM Press, New York

    Google Scholar 

  27. Griffin MR, Walker FJ, Iwane MK et al (2004) Epidemiology of respiratory infections in young children insights from the new vaccine surveillance network. Pediatr Infect Dis J 23:S188–S192

    Google Scholar 

  28. Glezen WP (2004) The changing epidemiology of respiratory syncytial virus and influenza impetus for new control measures. Pediatr Infect Dis J 23:S202–S206

    Google Scholar 

  29. Washburne JF, Bocchini JA Jr, Jamison RM (1992) Summertime respiratory syncytial virus infection: epidemiology and clinical manifestations. South Med J 85:579–583

    CAS  Google Scholar 

  30. Halstead DC, Jenkins SG (1998) Continuous non-seasonal epidemic of respiratory syncytial virus infection in the southeast United States. South Med J 91:433–436

    CAS  Google Scholar 

  31. Ottolini MG, Hemming VG (1997) Prevention and treatment recommendations for respiratory syncytial virus infection. Background and clinical experience 40 years after discovery. Drugs 54:867–884

    CAS  Google Scholar 

  32. Simoes EAF (1997) Respiratory syncytial virus infection: pathogenesis, treatment and prevention. Curr Opin Infect Dis 10:213–220

    Google Scholar 

  33. Holberg CJ, Wright AL, Martinez FD et al (1991) Risk factors for respiratory syncytial virus-associated lower respiratory illnesses in the first year of life. Am J Epidemiol 133:1135–1151

    CAS  Google Scholar 

  34. Glezen WP, Taber LH, Frank AL, Kasel JA (1986) Risk of primary infection and reinfection with respiratory syncytial virus. Am J Dis Child 140:543–546

    CAS  Google Scholar 

  35. Anderson LJ, Parker RA, Strikas RL (1990) Association between respiratory syncytial virus outbreaks and lower respiratory tract deaths of infants and young children. J Infect Dis 161:640–646

    CAS  Google Scholar 

  36. Nicholson KG (1996) Impact of influenza and respiratory syncytial virus on mortality in England and Wales form January 1975 to December 1990. Epidemiol Infect 116:51–63

    CAS  Google Scholar 

  37. Shay DK, Holman RC, Newman RD et al (1999) Bronchiolitis-associated hospitalizations among US children, 1980–1996. JAMA 282:1440–1446

    CAS  Google Scholar 

  38. Thompson WW, Shay DK, Weintraub E et al (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289:179–186

    Google Scholar 

  39. Breese Hall C, Powell KR, MacDonald NE et al (1986) Respiratory syncytial viral infection in children with compromised immune function. New Engl J Med 315:77–81

    Google Scholar 

  40. Englund JA, Sullivan CJ, Jordan MC et al (1988) Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med 109:203–208

    CAS  Google Scholar 

  41. Hertz MI, Englund JA, Snover D et al (1989) Respiratory syncytial virus-induced acute lung injury in adult patients with bone marrow transplants: a clinical approach and review of the literature. Medicine 68:269–281

    CAS  Google Scholar 

  42. Ebbert JO, Limper AH (2005) Respiratory syncytial virus pneomonitis in immunocompromised adults: clinical features and outcome. Respiration 72:263–269

    Google Scholar 

  43. Ljungman P (1997) Respiratory virus infections in bone marrow transplant recipients, the European perspective. Am J Med 102:44–47

    CAS  Google Scholar 

  44. Flamant C, Hallelel F, Nolent P et al (2005) Severe respiratory syncytial virus bronchiolitis in children: from short mechanical ventilation to extracorporeal membrane oxygenation. Eur J Pediatr 164:93–98

    Google Scholar 

  45. Hashem M, Hall CB (2003) Respiratory syncytial virus in healthy adults: the cost of a cold. J Clin Virol 27:14–21

    Google Scholar 

  46. Dowell SF, Anderson LJ, Gary HE Jr et al (1996) Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis 174:456–462

    CAS  Google Scholar 

  47. Mlinaric-Galinovic G, Falsey AR, Walsh EE (1996) Respiratory syncytial virus infection in the elderly. Eur J Clin Dis 15:777–781

    CAS  Google Scholar 

  48. Han LL, Alexander JP, Anderson LJ (1999) Respiratory syncytial virus pneumonia among the elderly: an assessment of the disease burden. J Infect Dis 179:25–30

    CAS  Google Scholar 

  49. Walsh EE, Peterson DR, Falsey AR (2004) Risk factors for severe respiratory syncytial virus infection in elderly persons. J Infect Dis 189:233–238

    Google Scholar 

  50. Falsey AR, Hennessey PA, Formica MA et al (2005) Respiratory syncytial virus infection in elderly and high-risk adults. New Engl J Med 352:1749–1759

    CAS  Google Scholar 

  51. Falsey AR, Walsh EE (2005) Respiratory syncytial virus infection in elderly adults. Drugs Aging 22:577–587

    Google Scholar 

  52. Zambon MC, Stockton JD, Clewley JP, Fleming DM (2001) Contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study. Lancet 358:1410–1416

    CAS  Google Scholar 

  53. Crowcroft NS, Cutts F, Zambon MC (1999) Respiratory syncytial virus: an underestimated cause of respiratory infection, with prospects for a vaccine. Commun Dis Public Health 2:234–241

    CAS  Google Scholar 

  54. Cane PA (2001) Molecular epidemiology of respiratory syncytial virus. Rev Med Virol 11:103–116

    CAS  Google Scholar 

  55. Melero JA (2007) Molecular biology of human respiratory syncytial virus. Perspect Med Virol 14:1–42

    CAS  Google Scholar 

  56. Ahmadian G, Chambers P, Easton AJ (1999) Detection and characterization of proteins encoded by the second ORF of the M2 gene of pneumoviruses. J Gen Virol 80:2011–2016

    CAS  Google Scholar 

  57. Melero JA, Garcia-Barreno B, Martinez I et al (1997) Antigenic structure, evolution and immunobiology of human respiratory syncytial virus attachment (G) protein. J Gen Virol 78:2411–2418

    CAS  Google Scholar 

  58. Krusat T, Streckert HJ (1997) Heparin-dependent attachment of respiratory syncytial virus (RSV) to host cells. Arch Virol 142:1247–1254

    CAS  Google Scholar 

  59. Harris J, Werling D (2003) Binding and entry of respiratory syncytial virus into host cells and initiation of the innate immune response. Cell Microbiol 5:671–680

    CAS  Google Scholar 

  60. Malhotra R, Ward M, Bright H et al (2003) Isolation and characterisation of potential respiratory syncytial virus receptor(s) on epithelial cells. Microbes Infect 5:123–133

    CAS  Google Scholar 

  61. Karron RA, Buonagurio DA, Georgiu AF et al (1997) Respiratory syncytial virus (RSV) SH and G proteins are not essential for viral replication in vitro: clinical evaluation and molecular characterization of a cold-passaged, attenuated RSV subgroup B mutant. Proc Natl Acad Sci USA 94:13961–13966

    CAS  Google Scholar 

  62. Kahn J, Schnell MJ, Buonocore L et al (1999) Recombinant vesicular stomatitis virus expressing respiratory syncytial virus (RSV) glycoproteins: RSV fusion protein can mediate infection and cell fusion. Virology 254:81–91

    CAS  Google Scholar 

  63. Feldman SA, Audet S, Beeler JA (2000) The fusion glycoprotein of human respiratory syncytial virus facilitates virus attachment and infectivity via an interaction with cellular heparan sulfate. J Virol 74:6442–6447

    CAS  Google Scholar 

  64. Techaarpornkul S, Barretto N, Peeples ME (2001) Functional analysis of recombinant respiratory syncytial virus deletion mutants lacking the small hydrophobic and/or attachment glycoprotein gene. J Virol 75:6825–6834

    CAS  Google Scholar 

  65. González-Reyes L, Ruiz-Argüello MB, García-Barreno B et al (2001) Cleavage of the human respiratory syncytial virus fusion protein at two distinct sites is required for activation of membrane fusion. Proc Natl Acad Sci USA 98:9859–9864

    Google Scholar 

  66. Zimmer G, Budz L, Herrler G (2001) Proteolytic activation of respiratory syncytial virus fusion protein. Cleavage at two furin consensus sequences. J Biol Chem 276:31642–31650

    CAS  Google Scholar 

  67. Behera AK, Matsuse H, Kumar M et al (2001) Blocking intercellular adhesion molecule-1 on human epithelial cells decreases respiratory syncytial virus infection. Biochem Biophys Res Commun 280:188–195

    CAS  Google Scholar 

  68. Tayyari F, Marchant D, Moraes TJ et al (2011) Identification of nucleolin as a cellular receptor for human respiratory syncytial virus. Nat Med 17:1132–1135

    CAS  Google Scholar 

  69. Fuentes S, Tran KC, Luthra P et al (2007) Function of the respiratory syncytial virus small hydrophobic protein. J Virol 81:8361–8366

    CAS  Google Scholar 

  70. Cowton VM, McGivern DR, Fearns R (2006) Unravelling the complexities of respiratory syncytial virus RNA synthesis. J Gen Virol 87:1805–1821

    CAS  Google Scholar 

  71. Noton SL, Cowton VM, Zack CR et al (2010) Evidence that the polymerase of respiratory syncytial virus initiates RNA replication in a nontemplated fashion. Proc Natl Acad Sci USA 107:10226–10231

    CAS  Google Scholar 

  72. Green N, Ott RD, Isaacs RJ, Fang H (2008) Cell-based assays to identify inhibitors of viral disease. Exp Opin Drug Discov 3:671–676

    CAS  Google Scholar 

  73. Stockwell BR (2004) Exploring biology with small organic molecules. Nature 432:846–854

    CAS  Google Scholar 

  74. Daelemans D, Pauwels R, De Clercq E, Pannecouque C (2011) A time-of-addition approach to target identification of antiviral compounds. Nat Protoc 6:925–933

    CAS  Google Scholar 

  75. Mason SW, Lawetz C, Gaudette Y et al (2004) Polyadenylation-dependent screening assay for respiratory syncytial virus RNA transcriptase activity and identification of an inhibitor. Nucleic Acids Res 32:4758–4767

    CAS  Google Scholar 

  76. Liuzzi M, Mason SW, Cartier M et al (2005) Inhibitors of respiratory syncytial virus replication target cotranscriptional mRNA guanylylation by viral RNA-dependent RNA polymerase. J Virol 79:13105–13115

    CAS  Google Scholar 

  77. Sudo K, Miyazaki Y, Kojima N et al (2005) YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action. Antiviral Res 65:125–131

    CAS  Google Scholar 

  78. Carter MC, Alber DG, Baxter RC et al (2006) 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus. J Med Chem 49:2311–2319

    CAS  Google Scholar 

  79. Henderson EA, Alber DG, Baxter RC et al (2007) 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus. The identification of a clinical candidate. J Med Chem 50:1685–1692

    CAS  Google Scholar 

  80. Chapman J, Abbott E, Alber DG et al (2007) RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrob Agents Chemother 51:3346–3353

    CAS  Google Scholar 

  81. Dent J, Grieve S, Harland R et al (2005) Multiple-dose safety and pharmacokinetics of A-60444, a novel compound active against respiratory syncytial virus (RSV). In: 45th interscience conference on antimicrobial agents chemotherapy, Washington, DC, Dec 16–19, Abstract F-483

    Google Scholar 

  82. Kimura K, Mori S, Tomita K et al (2000) Antiviral activity of NMSO3 against respiratory syncytial virus infection in vitro and in vivo. Antiviral Res 47:41–51

    CAS  Google Scholar 

  83. Wyde PR, Moylett EH, Chetty SN et al (2004) Comparison of the inhibition of human metapneumovirus and respiratory syncytial virus by NMSO3 in tissue culture assays. Antiviral Res 63:51–59

    CAS  Google Scholar 

  84. Kimura K, Ishioka K, Hashimoto K et al (2004) Isolation and characterization of NMSO3-resistant mutants of respiratory syncytial virus. Antiviral Res 61:165–171

    CAS  Google Scholar 

  85. Nakamura M, Terada M, Kamada M et al (2003) Mechanistic effect of NMSO3 on replication of human immunodeficiency virus. Antivir Chem Chemother 14:171–176

    CAS  Google Scholar 

  86. Dubovi EJ, Geratz JD, Tidwell RR (1980) Inhibition of respiratory syncytial virus by bis(5-amidino-2-benzimidazolyl)methane. Virology 103:502–504

    CAS  Google Scholar 

  87. Dubovi EJ, Geratz JD, Shaver SR, Tidwell RR (1981) Inhibition of respiratory syncytial virus-host cell interactions by mono- and diamidines. Antimicrob Agents Chemother 19:649–656

    CAS  Google Scholar 

  88. Tidwell RR, Geratz JD, Dubovi EJ (1983) Aromatic amidines. Comparison of their ability to block respiratory syncytial virus induced cell fusion and to inhibit plasmin, urokinase, thrombin, and trypsin. J Med Chem 26:294–298

    CAS  Google Scholar 

  89. Dubovi EJ, Geratz JD, Tidwell RR (1983) Enhancement of respiratory syncytial virus-induced cytopathology by trypsin, thrombin, and plasmin. Infect Immun 40:351–358

    CAS  Google Scholar 

  90. Cianci C, Yu K-L, Combrink K et al (2004) Orally active fusion inhibitor of respiratory syncytial virus. Antimicrob Agents Chemother 48:413–422

    CAS  Google Scholar 

  91. Tidwell RR, Geratz J, Dieter C et al (1984) Suppression of respiratory syncytial virus infection in cotton rats by bis(5-amidino-2-benzimidazolyl)methane. Antimicrob Agents Chemother 26:591–593

    CAS  Google Scholar 

  92. Ding W, Mitsner B, Krishnamurthy G et al (1998) Novel and specific respiratory syncytial virus inhibitors that target virus fusion. J Med Chem 41:2671–2675

    CAS  Google Scholar 

  93. Wyde PR, Moore-Poveda DK, O’Hara B et al (1998) CL387626 exhibits marked and unusual antiviral activity against respiratory syncytial virus in tissue culture and in cotton rats. Antiviral Res 38:31–42

    CAS  Google Scholar 

  94. Aulabaugh A, Ding W, Ellestad GA et al (2000) Inhibition of respiratory syncytial virus by a new class of chemotherapeutic agents. Drugs Future 25:287–294

    CAS  Google Scholar 

  95. Gazumyan A, Mitsner B, Ellestad GA (2000) Novel anti-RSV dianionic dendrimer-like compounds: design, synthesis and biological evaluation. Curr Pharm Des 6:525–546

    CAS  Google Scholar 

  96. Nikitenko A, Raifeld Y, Mitsner B, Newman H (2005) Pyrimidine containing RSV fusion inhibitors. Bioorg Med Chem Lett 15:427–430

    CAS  Google Scholar 

  97. Nikitenko A, Raifeld YE, Wang TZ (2001) The discovery of RFI-641 as a potent and selective inhibitor of the respiratory syncytial virus. Bioorg Med Chem Lett 11:1041–1044

    CAS  Google Scholar 

  98. Razinkov V, Gazumyan A, Nikitenko A et al (2001) RFI-641 inhibits entry of respiratory syncytial virus via interactions with fusion protein. Chem Biol 8:645–659

    CAS  Google Scholar 

  99. Razinkov V, Huntley C, Ellestad G et al (2002) RSV entry inhibitors block F-protein mediated fusion with model membranes. Antiviral Res 55:189–200

    CAS  Google Scholar 

  100. Huntley CC, Weiss WJ, Gazumyan A et al (2002) RFI-641, a potent respiratory syncytial virus inhibitor. Antimicrob Agents Chemother 46:841–847

    CAS  Google Scholar 

  101. Weiss WJ, Wyde P, Prince G et al (2000) Efficacy of RFI-641, a novel fusion inhibitor, in animal models of RSV infection. In: 40th interscience conference on antimicrobial agents and chemotherapy, Abstract H-186

    Google Scholar 

  102. Weiss WJ, Murphy T, Lynch ME et al (2003) Inhalation efficacy of RFI-641 in an African green monkey model of RSV infection. J Med Primatol 32:82–88

    CAS  Google Scholar 

  103. McKimm-Breschkin J (2000) VP-14637 ViroPharma. Curr Opin Investig Drugs 1:425–427

    CAS  Google Scholar 

  104. Nitz TJ, Pevear DC (1999) Preparation of heterocyclyl-substituted methylidynetrisphenol derivatives and related compounds for treating or preventing pneumovirus infection and associated diseases. World Patent Application WO1999/38508 A1

    Google Scholar 

  105. Wyde PR, Laquerre S, Chetty SN et al (2005) Antiviral efficacy of VP14637 against respiratory syncytial virus in vitro and in cotton rats following delivery by small droplet aerosol. Antiviral Res 68:18–26

    CAS  Google Scholar 

  106. Cianci C, Meanwell N, Krystal M (2005) Antiviral activity and molecular mechanism of an orally active respiratory syncytial virus fusion inhibitor. J Antimicrob Chemother 55:289–292

    CAS  Google Scholar 

  107. Yu K-L, Zhang Y, Civiello RL et al (2003) Fundamental structure-activity relationships associated with a new structural class of respiratory syncytial virus inhibitor. Bioorg Med Chem Lett 13:2141–2144

    CAS  Google Scholar 

  108. Yu K-L, Zhang Y, Civiello RL et al (2004) Respiratory syncytial virus inhibitors. Part 2: benzimidazol-2-one derivatives. Bioorg Med Chem Lett 14:1133–1137

    CAS  Google Scholar 

  109. Yu K-L, Wang XA, Civiello RL et al (2006) Respiratory syncytial virus fusion inhibitors. Part 3: water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo. Bioorg Med Chem Lett 16:1115–1122

    CAS  Google Scholar 

  110. Yu K-L, Sin N, Civiello RL et al (2007) Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability. Bioorg Med Chem Lett 17:895–901

    CAS  Google Scholar 

  111. Wang XA, Cianci CW, Yu K-L et al (2007) Respiratory syncytial virus fusion inhibitors. Part 5: optimization of benzimidazole substitution patterns towards derivatives with improved activity. Bioorg Med Chem Lett 17:4592–4598

    CAS  Google Scholar 

  112. Combrink KD, Gulgeze HB, Thuring JW et al (2007) Respiratory syncytial virus fusion inhibitors. Part 6: an examination of the effect of structural variation of the benzimidazol-2-one heterocycle moiety. Bioorg Med Chem Lett 17:4784–4790

    CAS  Google Scholar 

  113. Sin N, Venables BL, Combrink KD et al (2009) Respiratory syncytial virus fusion inhibitors. Part 7: structure-activity relationships associated with a series of isatin oximes that demonstrate antiviral activity in vivo. Bioorg Med Chem Lett 19:4857–4862

    CAS  Google Scholar 

  114. Cianci C, Genovesi EV, Lamb L et al (2004) Oral efficacy of a respiratory syncytial virus inhibitor in rodent models of infection. Antimicrob Agents Chemother 48:2448–2454

    CAS  Google Scholar 

  115. Pagani F, Sparatore F (1965) Benzotriazolylalkyl benzimidazoles and their dialkylaminoalkyl derivatives. Boll Chim Farm 104:427–431

    CAS  Google Scholar 

  116. Paglietti G, Boido V, Sparatore F (1975) Dialkylaminoalkylbenzimidazoles of pharmacological interest IV. Il Farmaco Ed Sci 30:505–511

    CAS  Google Scholar 

  117. Tonelli M, Paglietti G, Boido V et al (2008) Antiviral activity of benzimidazole derivatives. I. Antiviral activity of 1-substituted-2-[(benzotriazol-1/2-yl)methyl]benzimidazoles. Chem Biodivers 5:2386–2401

    CAS  Google Scholar 

  118. Andries K, Moeremans M, Gevers T et al (2003) Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus. Antiviral Res 60:209–219

    CAS  Google Scholar 

  119. Wyde PR, Chetty SN, Timmerman P et al (2003) Short duration aerosols of JNJ 2408068 (R170591) administered prophylactically or therapeutically protect cotton rats from experimental respiratory syncytial virus infection. Antiviral Res 60:221–231

    CAS  Google Scholar 

  120. Bonfanti J-F, Doublet F, Fortin J et al (2007) Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. Improving the pharmacokinetic profile using the structure-property relationship. J Med Chem 50:4572–4584

    CAS  Google Scholar 

  121. Bonfanti JF, Meyer C, Doublet F et al (2008) Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121). J Med Chem 51:875–896

    CAS  Google Scholar 

  122. Rouan M-C, Gevers T, Roymans D et al (2010) Pharmacokinetics-pharmacodynamics of a respiratory syncytial virus fusion inhibitor in the cotton rat model. Antimicrob Agents Chemother 54:4534–4539

    CAS  Google Scholar 

  123. Olszewska W, Ispas G, Schnoeller C et al (2011) Antiviral and lung protective activity of a novel RSV fusion inhibitor in a mouse model. Eur Respir J 38:401–408

    CAS  Google Scholar 

  124. Bond S, Sanford VA, Lambert JN et al (2005) Preparation of polycyclic agents for the treatment of respiratory syncytial virus infections. World Patent Application WO2005/061513 A1

    Google Scholar 

  125. Mitchell JP, Draffan AG, Sanford VA et al (2008) Polycyclic imidazole derivatives as antiviral agents and their preparation, pharmaceutical compositions and use in the treatment of RSV infections. World Patent Application WO2008/037011 A1

    Google Scholar 

  126. Mitchell JP, Pitt G, Draffan AG, Mayes PA, Andrau L, Anderson K (2011) Compounds for treating respiratory syncytial virus infections. World Patent Application WO2011/094823 A1

    Google Scholar 

  127. Information available at Biota’s website http://www.biota.com.au/uploaded/154/1021724_171101uscorporatepresenta.pdf

  128. Lundin A, Bergstroem T, Bendrioua L et al (2010) Two novel fusion inhibitors of human respiratory syncytial virus. Antiviral Res 88:317–332

    CAS  Google Scholar 

  129. Morton CJ, Cameron R, Lawrence LJ et al (2003) Structural characterization of respiratory syncytial virus fusion inhibitor escape mutants: homology model of the F protein and a syncytium formation assay. Virology 311:275–288

    CAS  Google Scholar 

  130. Douglas JL, Panis ML, Ho E et al (2003) Inhibition of respiratory syncytial virus fusion by the small molecule VP-14637 via specific interactions with F protein. J Virol 77:5054–5064

    CAS  Google Scholar 

  131. Douglas JL, Panis ML, Ho E et al (2005) Small molecules VP-14637 and JNJ-2408068 inhibit respiratory syncytial virus fusion by similar mechanisms. Antimicrob Agents Chemother 49:2460–2466

    CAS  Google Scholar 

  132. Dischino DD, Cianci CW, Civiello R et al (2003) Development of a photoaffinity label for respiratory syncytial virus inhibitors. J Label Compd Radiopharm 46:1105–1116

    CAS  Google Scholar 

  133. Cianci C, Langley DR, Dischino DD et al (2004) Targeting a binding pocket within the trimer-of-hairpins: small-molecule inhibition of viral fusion. Proc Natl Acad Sci USA 101:15046–15051

    CAS  Google Scholar 

  134. Roymans D, De Bondt HL, Arnoult E et al (2010) Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein. Proc Natl Acad Sci USA 107:308–313

    CAS  Google Scholar 

  135. Donald JE, Zhang Y, Fiorin G et al (2011) Transmembrane orientation and possible role of the fusogenic peptide from parainfluenza virus 5 (PIV5) in promoting fusion. Proc Natl Acad Sci USA 108:3958–3963

    CAS  Google Scholar 

  136. Markosyan RM, Cohen FS, Melikyan GB (2003) HIV-1 envelope proteins complete their folding into six-helix bundles immediately after fusion pore formation. Mol Biol Cell 14:926–938

    CAS  Google Scholar 

  137. Markosyan RM, Leung MY, Cohen FS (2009) The six-helix bundle of human immunodeficiency virus env controls pore formation and enlargement and is initiated at residues proximal to the hairpin turn. J Virol 83:10048–10057

    CAS  Google Scholar 

  138. Lee KK (2010) Architecture of a nascent viral fusion pore. EMBO J 29:1299–1311

    CAS  Google Scholar 

  139. Imai M, Mizuno T, Kawasaki K (2006) Membrane fusion by single influenza hemagglutinin trimers. Kinetic evidence from image analysis of hemagglutinin-reconstituted vesicles. J Biol Chem 281:12729–12735

    CAS  Google Scholar 

  140. Kemble GW, Danieli T, White JM (1994) Lipid-anchored influenza hemagglutinin promotes hemifusion, not complete fusion. Cell 76:383–391

    CAS  Google Scholar 

  141. Steinhauer DA, Wharton SA, Skehel JJ, Wiley DC (1995) Studies of the membrane fusion activities of fusion peptide mutants of influenza virus hemagglutinin. J Virol 69:6643–6651

    CAS  Google Scholar 

  142. Qiao H, Armstrong RT, Melikyan GB et al (1999) A specific point mutant at position 1 of the influenza hemagglutinin fusion peptide displays a hemifusion phenotype. Mol Biol Cell 10:2759–2769

    CAS  Google Scholar 

  143. Dobay MP, Dobay A, Bantang J, Mendoza E (2011) How many trimers? Modeling influenza virus fusion yields a minimum aggregate size of six trimers, there of which are fusogenic. Mol Biosyst 7:2741–2749

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicinal Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA

    Nicholas A. Meanwell

  2. Department of Computer-Aided Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT, 06492, USA

    David R. Langley

Authors
  1. Nicholas A. Meanwell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David R. Langley
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas A. Meanwell .

Editor information

Editors and Affiliations

  1. , Global Pharmaceutical R & D, Abbott Laboratories, Dept R4N6 / Bldg AP10-3, Abbott Park Rd 100, Abbott Park, 60064, Illinois, USA

    Michael D. Wendt

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Meanwell, N.A., Langley, D.R. (2012). Inhibitors of Protein-Protein Interactions in Paramyxovirus Fusion: A Focus on Respiratory Syncytial Virus. In: Wendt, M. (eds) Protein-Protein Interactions. Topics in Medicinal Chemistry, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-28965-1_5

Download citation

Publish with us

Policies and ethics

Search

Navigation