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Recent Advances in Developing Antiviral Therapies for Respiratory Syncytial Virus

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Abstract

Respiratory syncytial virus (RSV) infection presents a significant health challenge in small children, the elderly and immunocompromised patients. There is still a high unmet medical need among patients with RSV infection, and no specific antiviral therapy is available. The only approved agents are palivizumab, which has to be given prophylactically, mainly in high-risk infants, and ribavirin, which is rarely used due to toxicity concerns and questionable benefits. Efforts to develop new antiviral agents have been hampered by the perceived need for high safety hurdles in pediatric patient populations use and the lack of well-characterized druggable targets. Despite these challenges, significant progress has been made in discovering multiple classes of inhibitors targeting various stages of the viral life cycle. Several recent proof-of-concept human studies with specific antivirals have shown promising results and completely reinvigorated the field. In this review we discuss the current status of RSV drug development, remaining challenges and future directions.

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References

  1. Nair H, Verma VR, Theodoratou E, Zgaga L, Huda T, Simoes EA, Wright PF, Rudan I, Campbell H (2011) An evaluation of the emerging interventions against Respiratory Syncytial Virus (RSV)-associated acute lower respiratory infections in children. BMC Public Health 11[Suppl 3]:S30. doi:10.1186/1471-2458-11-S3-S30

    Article  Google Scholar 

  2. Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, O’Brien KL, Roca A, Wright PF, Bruce N, Chandran A, Theodoratou E, Sutanto A, Sedyaningsih ER, Ngama M, Munywoki PK, Kartasasmita C, Simoes EA, Rudan I, Weber MW, Campbell H (2010) Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 375(9725):1545–1555. doi:10.1016/S0140-6736(10)60206-1

    Article  Google Scholar 

  3. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, Auinger P, Griffin MR, Poehling KA, Erdman D, Grijalva CG, Zhu Y, Szilagyi P (2009) The burden of respiratory syncytial virus infection in young children. N Engl J Med 360(6):588–598. doi:10.1056/NEJMoa0804877

    Article  CAS  Google Scholar 

  4. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE (2005) Respiratory syncytial virus infection in elderly and high-risk adults. N Engl J Med 352(17):1749–1759. doi:10.1056/NEJMoa043951

    Article  CAS  Google Scholar 

  5. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, Fukuda K (2003) Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA 289(2):179–186

    Article  Google Scholar 

  6. Weigt SS, Gregson AL, Deng JC, Lynch JP 3rd, Belperio JA (2011) Respiratory viral infections in hematopoietic stem cell and solid organ transplant recipients. Semin Respir Crit Care Med 32(4):471–493. doi:10.1055/s-0031-1283286

    Article  Google Scholar 

  7. Meissner HC, Rennels MB, Pickering LK, Hall CB (2004) Risk of severe respiratory syncytial virus disease, identification of high risk infants and recommendations for prophylaxis with palivizumab. Pediatr Infect Dis J 23(3):284–285

    Article  Google Scholar 

  8. Chemaly RF, Aitken SL, Wolfe CR, Jain R, Boeckh MJ (2016) Aerosolized ribavirin: the most expensive drug for pneumonia. Transpl Infect Dis 18(4):634–636. doi:10.1111/tid.12551

    Article  CAS  Google Scholar 

  9. Anderson LJ, Hierholzer JC, Tsou C, Hendry RM, Fernie BF, Stone Y, McIntosh K (1985) Antigenic characterization of respiratory syncytial virus strains with monoclonal antibodies. J Infect Dis 151(4):626–633

    Article  CAS  Google Scholar 

  10. Spann KM, Tran KC, Collins PL (2005) Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-kappaB, and proinflammatory cytokines. J Virol 79(9):5353–5362. doi:10.1128/JVI.79.9.5353-5362.2005

    Article  CAS  Google Scholar 

  11. Swedan S, Andrews J, Majumdar T, Musiyenko A, Barik S (2011) Multiple functional domains and complexes of the two nonstructural proteins of human respiratory syncytial virus contribute to interferon suppression and cellular location. J Virol 85(19):10090–10100. doi:10.1128/JVI.00413-11

    Article  CAS  Google Scholar 

  12. Bitko V, Shulyayeva O, Mazumder B, Musiyenko A, Ramaswamy M, Look DC, Barik S (2007) Nonstructural proteins of respiratory syncytial virus suppress premature apoptosis by an NF-kappaB-dependent, interferon-independent mechanism and facilitate virus growth. J Virol 81(4):1786–1795. doi:10.1128/JVI.01420-06

    Article  CAS  Google Scholar 

  13. Feldman SA, Hendry RM, Beeler JA (1999) Identification of a linear heparin binding domain for human respiratory syncytial virus attachment glycoprotein G. J Virol 73(8):6610–6617

    CAS  Google Scholar 

  14. 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(14):6442–6447

    Article  CAS  Google Scholar 

  15. Johnson SM, McNally BA, Ioannidis I, Flano E, Teng MN, Oomens AG, Walsh EE, Peeples ME (2015) Respiratory syncytial virus uses CX3CR1 as a receptor on primary human airway epithelial cultures. PLoS Pathog 11(12):e1005318. doi:10.1371/journal.ppat.1005318

    Article  Google Scholar 

  16. Chirkova T, Lin S, Oomens AG, Gaston KA, Boyoglu-Barnum S, Meng J, Stobart CC, Cotton CU, Hartert TV, Moore ML, Ziady AG, Anderson LJ (2015) CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells. J Gen Virol 96(9):2543–2556. doi:10.1099/vir.0.000218

    Article  CAS  Google Scholar 

  17. Jeong KI, Piepenhagen PA, Kishko M, DiNapoli JM, Groppo RP, Zhang L, Almond J, Kleanthous H, Delagrave S, Parrington M (2015) CX3CR1 Is expressed in differentiated human ciliated airway cells and co-localizes with respiratory syncytial virus on cilia in a g protein-dependent manner. PLoS One 10(6):e0130517. doi:10.1371/journal.pone.0130517

    Article  Google Scholar 

  18. DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, Harrison L, Meeking P, Mann A, Moane E, Oxford J, Pareek R, Moore R, Walsh E, Studholme R, Dorsett P, Alvarez R, Lambkin-Williams R (2010) Viral load drives disease in humans experimentally infected with respiratory syncytial virus. Am J Respir Crit Care Med 182(10):1305–1314. doi:10.1164/rccm.201002-0221OC

    Article  CAS  Google Scholar 

  19. Buckingham SC, Bush AJ, Devincenzo JP (2000) Nasal quantity of respiratory syncytical virus correlates with disease severity in hospitalized infants. Pediatr Infect Dis J 19(2):113–117

    Article  CAS  Google Scholar 

  20. Hallak LK, Spillmann D, Collins PL, Peeples ME (2000) Glycosaminoglycan sulfation requirements for respiratory syncytial virus infection. J Virol 74(22):10508–10513

    Article  CAS  Google Scholar 

  21. Fuentes S, Crim RL, Beeler J, Teng MN, Golding H, Khurana S (2013) Development of a simple, rapid, sensitive, high-throughput luciferase reporter based microneutralization test for measurement of virus neutralizing antibodies following respiratory syncytial virus vaccination and infection. Vaccine 31(37):3987–3994. doi:10.1016/j.vaccine.2013.05.088

    Article  CAS  Google Scholar 

  22. Tiong-Yip CL, Plant H, Sharpe P, Fan J, Rich K, Gorseth E, Yu Q (2014) Development of a high-throughput replicon assay for the identification of respiratory syncytial virus inhibitors. Antivir Res 101:75–81. doi:10.1016/j.antiviral.2013.11.003

    Article  CAS  Google Scholar 

  23. Bem RA, Domachowske JB, Rosenberg HF (2011) Animal models of human respiratory syncytial virus disease. Am J Physiol Lung Cell Mol Physiol 301(2):L148–156. doi:10.1152/ajplung.00065.2011

    Article  CAS  Google Scholar 

  24. Boukhvalova MS, Prince GA, Blanco JC (2009) The cotton rat model of respiratory viral infections. Biologicals 37(3):152–159. doi:10.1016/j.biologicals.2009.02.017

    Article  CAS  Google Scholar 

  25. Taylor G, Stott EJ, Hughes M, Collins AP (1984) Respiratory syncytial virus infection in mice. Infect Immun 43(2):649–655

    CAS  Google Scholar 

  26. Ispas G, Koul A, Verbeeck J, Sheehan J, Sanders-Beer B, Roymans D, Andries K, Rouan MC, De Jonghe S, Bonfanti JF, Vanstockem M, Simmen K, Verloes R (2015) Antiviral activity of tmc353121, a respiratory syncytial virus (rsv) fusion inhibitor, in a non-human primate model. PLoS One 10(5):e0126959. doi:10.1371/journal.pone.0126959

    Article  Google Scholar 

  27. Deval J, Hong J, Wang G, Taylor J, Smith LK, Fung A, Stevens SK, Liu H, Jin Z, Dyatkina N, Prhavc M, Stoycheva AD, Serebryany V, Liu J, Smith DB, Tam Y, Zhang Q, Moore ML, Fearns R, Chanda SM, Blatt LM, Symons JA, Beigelman L (2015) Molecular basis for the selective inhibition of respiratory syncytial virus rna polymerase by 2′-fluoro-4′-chloromethyl-cytidine triphosphate. PLoS Pathog 11(6):e1004995. doi:10.1371/journal.ppat.1004995

    Article  Google Scholar 

  28. McInnes E, Sopp P, Howard CJ, Taylor G (1999) Phenotypic analysis of local cellular responses in calves infected with bovine respiratory syncytial virus. Immunology 96(3):396–403

    Article  CAS  Google Scholar 

  29. Derscheid RJ, Ackermann MR (2012) Perinatal lamb model of respiratory syncytial virus (RSV) infection. Viruses 4(10):2359–2378. doi:10.3390/v4102359

    Article  CAS  Google Scholar 

  30. Detalle L (2014) Delivery of ALX-0171 by inhalation greatly reduces disease burden in a neonatal lamb RSV infection model. Paper presented at the 9th International Respiratory Syncytial Virus Symposium, Cape Town, South Africa, 13 November 2014

  31. DeVincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L, Farrell E, McBride S, Lambkin-Williams R, Jordan R, Xin Y, Ramanathan S, O’Riordan T, Lewis SA, Li X, Toback SL, Lin SL, Chien JW (2014) Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 371(8):711–722. doi:10.1056/NEJMoa1401184

    Article  Google Scholar 

  32. Israel S, Rusch S, DeVincenzo J, Boyers A, Fok-Seang J, Huntjens D, Lounis N, Mariёn K, Stevens M, Verloes R (2016) Effect of oral jnj-53718678 (jnj-678) on disease severity in healthy adult volunteers experimentally inoculated with live respiratory syncytial virus (rsv): A placebo-controlled challenge study. Paper presented at IDWeek, New Orleans, LA, 26–30 October 2016

  33. Aviragen Therapeutics Inc. (2017) Press release on 1 February 2017. Aviragen therapeutics announces top-line results from phase 2a RSV challenge study of BTA585. http://investors.aviragentherapeutics.com/releasedetail.cfm?ReleaseID=1010067

  34. http://www.clinicaltrials.gov

  35. ReViral (2016) Press release on 31 October 2016. ReViral initiates Phase 1 clinical trial of potent oral inhibitor against Respiratory Syncytial Virus. http://www.reviral.co.uk/news/23/79/ReViral-initiates-Phase-1-clinical-trial-of-potent-oral-inhibitor-against-Respiratory-Syncytial-Virus.html

  36. DeVincenzo JP, McClure MW, Symons JA, Fathi H, Westland C, Chanda S, Lambkin-Williams R, Smith P, Zhang Q, Beigelman L, Blatt LM, Fry J (2015) Activity of oral als-008176 in a respiratory syncytial virus challenge study. N Engl J Med 373(21):2048–2058. doi:10.1056/NEJMoa1413275

    Article  CAS  Google Scholar 

  37. Coates M, Brookes D, Allen H, Fordyce E, Colley T, Hunt F, Onion S, Knowles I, Murray PJ, Ito K, Strong P, Rapeport G (2016) Preclinical characterization of PC786, a potent antiviral inhibitor of respiratory syncytial virus replication. Paper presented at the XVIII international symposium on respiratory viral infections, Lisbon, Portugal, 31 March–2 April 2016

  38. Ablynx (2017) Press release on 11 January 2017. Ablynx initiates the phase IIb "RESPIRE" study of its wholly-owned, first-in-class, inhaled anti-RSV nanobody, ALX-0171, for the treatment of RSV infections in hospitalised infants. http://hugin.info/137912/R/2070650/778002.pdf

  39. Gottlieb J, Zamora MR, Hodges T, Musk AW, Sommerwerk U, Dilling D, Arcasoy S, DeVincenzo J, Karsten V, Shah S, Bettencourt BR, Cehelsky J, Nochur S, Gollob J, Vaishnaw A, Simon AR, Glanville AR (2016) ALN-RSV01 for prevention of bronchiolitis obliterans syndrome after respiratory syncytial virus infection in lung transplant recipients. J Heart Lung Transpl 35(2):213–221. doi:10.1016/j.healun.2015.08.012

    Article  Google Scholar 

  40. Hemming VG, Prince GA, Horswood RL, London WJ, Murphy BR, Walsh EE, Fischer GW, Weisman LE, Baron PA, Chanock RM (1985) Studies of passive immunotherapy for infections of respiratory syncytial virus in the respiratory tract of a primate model. J Infect Dis 152(5):1083–1087

    Article  CAS  Google Scholar 

  41. Prince GA, Horswood RL, Chanock RM (1985) Quantitative aspects of passive immunity to respiratory syncytial virus infection in infant cotton rats. J Virol 55(3):517–520

    CAS  Google Scholar 

  42. The PREVENT Study Group (1997) Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 99(1):93–99

    Article  Google Scholar 

  43. Johnson S, Oliver C, Prince GA, Hemming VG, Pfarr DS, Wang SC, Dormitzer M, O’Grady J, Koenig S, Tamura JK, Woods R, Bansal G, Couchenour D, Tsao E, Hall WC, Young JF (1997) Development of a humanized monoclonal antibody (MEDI-493) with potent in vitro and in vivo activity against respiratory syncytial virus. J Infect Dis 176(5):1215–1224

    Article  CAS  Google Scholar 

  44. The IMpact-RSV Study Group (1998) Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 102(3 Pt 1):531–537

    Article  Google Scholar 

  45. Abarca K, Jung E, Fernandez P, Zhao L, Harris B, Connor EM, Losonsky GA, Motavizumab Study G (2009) Safety, tolerability, pharmacokinetics, and immunogenicity of motavizumab, a humanized, enhanced-potency monoclonal antibody for the prevention of respiratory syncytial virus infection in at-risk children. Pediatr Infect Dis J 28(4):267–272. doi:10.1097/INF.0b013e31818ffd03

    Article  Google Scholar 

  46. Wu H, Pfarr DS, Johnson S, Brewah YA, Woods RM, Patel NK, White WI, Young JF, Kiener PA (2007) Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. J Mol Biol 368(3):652–665. doi:10.1016/j.jmb.2007.02.024

    Article  CAS  Google Scholar 

  47. Carbonell-Estrany X, Simoes EA, Dagan R, Hall CB, Harris B, Hultquist M, Connor EM, Losonsky GA, Motavizumab Study G (2010) Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a noninferiority trial. Pediatrics 125(1):e35–51. doi:10.1542/peds.2008-1036

    Article  Google Scholar 

  48. Ramilo O, Lagos R, Saez-Llorens X, Suzich J, Wang CK, Jensen KM, Harris BS, Losonsky GA, Griffin MP, Motavizumab Study G (2014) Motavizumab treatment of infants hospitalized with respiratory syncytial virus infection does not decrease viral load or severity of illness. Pediatr Infect Dis J 33(7):703–709. doi:10.1097/INF.0000000000000240

    Article  Google Scholar 

  49. Griffin MP, Khan A, Jensen KM, Takas TF, Dubovsky F, Robbie GJ (2015) A passive vaccine approach to rsv prophylaxis for all infants: Results of a phase 1 study in healthy adult volunteers. Paper presented at ID Week, San Diego, CA, 7–11 October 2015

  50. Detalle L, Stohr T, Palomo C, Piedra PA, Gilbert BE, Mas V, Millar A, Power UF, Stortelers C, Allosery K, Melero JA, Depla E (2016) Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. Antimicrob Agents Chemother 60(1):6–13. doi:10.1128/AAC.01802-15

    Article  CAS  Google Scholar 

  51. Mackman RL, Sangi M, Sperandio D, Parrish JP, Eisenberg E, Perron M, Hui H, Zhang L, Siegel D, Yang H, Saunders O, Boojamra C, Lee G, Samuel D, Babaoglu K, Carey A, Gilbert BE, Piedra PA, Strickley R, Iwata Q, Hayes J, Stray K, Kinkade A, Theodore D, Jordan R, Desai M, Cihlar T (2015) Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study. J Med Chem 58(4):1630–1643. doi:10.1021/jm5017768

    Article  CAS  Google Scholar 

  52. Douglas JL, Panis ML, Ho E, Lin KY, Krawczyk SH, Grant DM, Cai R, Swaminathan S, Chen X, Cihlar T (2005) Small molecules VP-14637 and JNJ-2408068 inhibit respiratory syncytial virus fusion by similar mechanisms. Antimicrob Agents Chemother 49(6):2460–2466. doi:10.1128/AAC.49.6.2460-2466.2005

    Article  CAS  Google Scholar 

  53. Babaoglu K, Boojamra CG, Eisenberg EJ, Hui HC, Mackman RL, Parrish JP, Sangi M, Saunders OL, Siegel D, Sperandio D, Yang H (2011) Pyrazolo[1,5-A]pyrimidines as antiviral agents. WO patent WO2011/163518, 29 Dec 2011

  54. Collins PL, Hill MG, Cristina J, Grosfeld H (1996) Transcription elongation factor of respiratory syncytial virus, a nonsegmented negative-strand RNA virus. Proc Natl Acad Sci USA 93(1):81–85

    Article  CAS  Google Scholar 

  55. Jin F, Chien JW, Mackman R, Lewis S, Bayly S, Ramantha S (2014) Single and multiple dose-ranging evaluation of safety and pharmacokinetics of the RSV fusion inhibitor GS-5806. Poster A-009. Paper presented at the 54th interscience conference on antimicrobial agents and chemotherapy, Washington DC, 2–6 September 2014

  56. Xin Y, DeVincenzo JP, Lewis SA, Jin F, Swift F, Renton N, Mackman RL, Jordan R, Toback SL, Li X, Lin S-L, Chien JW, Tamanathan S (2014) Exposure-antiviral activity evaluation of GS-5806 in a RSV- challenge study in healthy subjects. Poster 72. Paper presented at the 54th interscience conference on antimicrobial agents and chemotherapy, Washington DC, 2–6 September 2014

  57. Bond S, Sanford VA, Lambert JN, Lim CY, Mitchell JP, Draffan AG, Nearn RH (2005) Preparation of polycyclic agents for the treatment of respiratory syncytial virus infections. WO patent WO2005/061513, 7 July 2005

  58. Mitchell JP, Draffan AG, Sanford VA, Bond S, Lim CY, Mayes PA (2008) Polycyclic imidazole derivatives as antiviral agents and their preparation, pharmaceutical compositions and use in the treatment of RSV infections. WO patent WO2008/037011, 3 Apr 2008

  59. Mitchell JP, Pitt G, Draffan AG, Mayes PA, Andrau L, Anderson K (2011) Preparation of nitrogen-containing tricyclic heterocyclic compounds for treating respiratory syncytial virus infections. WO patent WO2011/094823, 11 Aug 2011

  60. Morton CJ, Cameron R, Lawrence LJ, Lin B, Lowe M, Luttick A, Mason A, McKimm-Breschkin J, Parker MW, Ryan J, Smout M, Sullivan J, Tucker SP, Young PR (2003) Structural characterization of respiratory syncytial virus fusion inhibitor escape mutants: homology model of the F protein and a syncytium formation assay. Virology 311(2):275–288

    Article  CAS  Google Scholar 

  61. Cox R, Plemper RK (2016) Structure-guided design of small-molecule therapeutics against RSV disease. Expert Opin Drug Discov 11(6):543–556

    Article  CAS  Google Scholar 

  62. Bond S, Draffan AG, Fenner JE, Lambert J, Lim CY, Lin B, Luttick A, Mitchell JP, Morton CJ, Nearn RH, Sanford V, Anderson KH, Mayes PA, Tucker SP (2015) 1,2,3,9b-Tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 2: identification of BTA9881 as a preclinical candidate. Bioorg Med Chem Lett 25(4):976–981. doi:10.1016/j.bmcl.2014.11.024

    Article  CAS  Google Scholar 

  63. Bond S, Draffan AG, Fenner JE, Lambert J, Lim CY, Lin B, Luttick A, Mitchell JP, Morton CJ, Nearn RH, Sanford V, Stanislawski PC, Tucker SP (2015) The discovery of 1,2,3,9b-tetrahydro-5H-imidazo[2,1-a]isoindol-5-ones as a new class of respiratory syncytial virus (RSV) fusion inhibitors. Part 1. Bioorg Med Chem Lett 25(4):969–975. doi:10.1016/j.bmcl.2014.11.018

    Article  CAS  Google Scholar 

  64. BioSpace.com. http://www.biospace.com/News/aviragen-delays-further-enrollment-in-phase-iia/421076/source=TopBreaking?intcid=homepage-seekernewssection-tabtopbreakingnews (published on Globe Newswire, Atlanta, GA, 26 May 2016)

  65. Paglietti G, Boido V, Sparatore F (1975) [Dialkylaminoalkylbenzimidazoles of pharmacological importance IV]. Farmaco Sci 30(6):505–511

    CAS  Google Scholar 

  66. Pagani F, Sparatore F (1965) Benzotriazolyl-alkyl-benzimidazoles and their dialkyl-aminoalkyl derivatives. Boll Chim Farm 104(7):427–431

    CAS  Google Scholar 

  67. Yu KL, Zhang Y, Civiello RL, Kadow KF, Cianci C, Krystal M, Meanwell NA (2003) Fundamental structure-activity relationships associated with a new structural class of respiratory syncytial virus inhibitor. Bioorg Med Chem Lett 13(13):2141–2144

    Article  CAS  Google Scholar 

  68. Yu KL, Zhang Y, Civiello RL, Trehan AK, Pearce BC, Yin Z, Combrink KD, Gulgeze HB, Wang XA, Kadow KF, Cianci CW, Krystal M, Meanwell NA (2004) Respiratory syncytial virus inhibitors. Part 2: benzimidazol-2-one derivatives. Bioorg Med Chem Lett 14(5):1133–1137. doi:10.1016/j.bmcl.2003.12.072

    Article  CAS  Google Scholar 

  69. Yu KL, Wang XA, Civiello RL, Trehan AK, Pearce BC, Yin Z, Combrink KD, Gulgeze HB, Zhang Y, Kadow KF, Cianci CW, Clarke J, Genovesi EV, Medina I, Lamb L, Wyde PR, Krystal M, Meanwell NA (2006) Respiratory syncytial virus fusion inhibitors. Part 3: water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo. Bioorg Med Chem Lett 16(5):1115–1122. doi:10.1016/j.bmcl.2005.11.109

    Article  CAS  Google Scholar 

  70. Yu KL, Sin N, Civiello RL, Wang XA, Combrink KD, Gulgeze HB, Venables BL, Wright JJ, Dalterio RA, Zadjura L, Marino A, Dando S, D’Arienzo C, Kadow KF, Cianci CW, Li Z, Clarke J, Genovesi EV, Medina I, Lamb L, Colonno RJ, Yang Z, Krystal M, Meanwell NA (2007) Respiratory syncytial virus fusion inhibitors. Part 4: optimization for oral bioavailability. Bioorg Med Chem Lett 17(4):895–901. doi:10.1016/j.bmcl.2006.11.063

    Article  CAS  Google Scholar 

  71. 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(3):289–292. doi:10.1093/jac/dkh558

    Article  CAS  Google Scholar 

  72. Cianci C, Genovesi EV, Lamb L, Medina I, Yang Z, Zadjura L, Yang H, D’Arienzo C, Sin N, Yu KL, Combrink K, Li Z, Colonno R, Meanwell N, Clark J, Krystal M (2004) Oral efficacy of a respiratory syncytial virus inhibitor in rodent models of infection. Antimicrob Agents Chemother 48(7):2448–2454. doi:10.1128/AAC.48.7.2448-2454.2004

    Article  CAS  Google Scholar 

  73. Bonfanti J-F, Andries KJL, Janssens FE, Sommen FM, Guillemont JEG, Lacrampe JFA (2005) Preparation of piperidine-amino-benzimidazole derivatives as inhibitors of respiratory syncytial virus replication. WO patent WO2005/058873, 3 June 2005

  74. Janssens FE, Meersman KPM-J, Sommen FM, Guillemont JEG, Lacrampe JFA, Andries KJLM (2001) Preparation of benzimidazoles as respiratory syncytial virus replication inhibitors. WO patent WO2001/000611, 1 Apr 2001

  75. Andries K, Moeremans M, Gevers T, Willebrords R, Sommen C, Lacrampe J, Janssens F, Wyde PR (2003) Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus. Antiviral Res 60(3):209–219

    Article  CAS  Google Scholar 

  76. Bonfanti JF, Meyer C, Doublet F, Fortin J, Muller P, Queguiner L, Gevers T, Janssens P, Szel H, Willebrords R, Timmerman P, Wuyts K, van Remoortere P, Janssens F, Wigerinck P, Andries K (2008) Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121). J Med Chem 51(4):875–896. doi:10.1021/jm701284j

    Article  CAS  Google Scholar 

  77. Bonfanti JF, Doublet F, Fortin J, Lacrampe J, Guillemont J, Muller P, Queguiner L, Arnoult E, Gevers T, Janssens P, Szel H, Willebrords R, Timmerman P, Wuyts K, Janssens F, Sommen C, Wigerinck P, Andries K (2007) Selection of a respiratory syncytial virus fusion inhibitor clinical candidate, part 1: improving the pharmacokinetic profile using the structure-property relationship. J Med Chem 50(19):4572–4584. doi:10.1021/jm070143x

    Article  CAS  Google Scholar 

  78. Vendeville S (2016) Discovery of a potent and orally bioavailable fusion inhibitor of respiratory syncytial virus (RSV). Paper presented at the 11th Annual Drug Discovery Chemistry Symposia, San Diego, CA, 22 April 2016

  79. 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(2):247–254

    Article  Google Scholar 

  80. Nitz TJ, Pevear DC (1999) Preparation of heterocyclyl-substituted methylidynetrisphenol derivatives and related compounds for treating or preventing pneumovirus infection and associated diseases. WO patent WO1999/038508, 5 Aug 1999

  81. McKimm-Breschkin J (2000) VP-14637 ViroPharma. Curr Opin Investig Drugs 1(4):425–427

    CAS  Google Scholar 

  82. Douglas JL, Panis ML, Ho E, Lin KY, Krawczyk SH, Grant DM, Cai R, Swaminathan S, Cihlar T (2003) Inhibition of respiratory syncytial virus fusion by the small molecule VP-14637 via specific interactions with F protein. J Virol 77(9):5054–5064

    Article  CAS  Google Scholar 

  83. Wyde PR, Laquerre S, Chetty SN, Gilbert BE, Nitz TJ, Pevear DC (2005) Antiviral efficacy of VP14637 against respiratory syncytial virus in vitro and in cotton rats following delivery by small droplet aerosol. Antivir Res 68(1):18–26. doi:10.1016/j.antiviral.2005.06.009

    Article  CAS  Google Scholar 

  84. Feng S, Hong D, Wang B, Zheng X, Miao K, Wang L, Yun H, Gao L, Zhao S, Shen HC (2015) Discovery of imidazopyridine derivatives as highly potent respiratory syncytial virus fusion inhibitors. ACS Med Chem Lett 6(3):359–362. doi:10.1021/acsmedchemlett.5b00008

    Article  CAS  Google Scholar 

  85. Zheng X, Wang L, Wang B, Miao K, Xiang K, Feng S, Gao L, Shen HC, Yun H (2016) Discovery of piperazinylquinoline derivatives as novel respiratory syncytial virus fusion inhibitors. ACS Med Chem Lett 7(6):558–562. doi:10.1021/acsmedchemlett.5b00234

    Article  CAS  Google Scholar 

  86. Ark Biosciences (2014) Press release on Jun 6, 2014. Ark Biosciences licenses novel drug candidate from Roche for potential treatment of RSV infection. http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=547973

  87. Carter M, Henderson E, Kelsey R, Wilson L, Chanbers P, Taylor D, Tyms S (2004) Benzodiazepine derivatives and pharmaceutical compositions containing them. WO patent WO2004/026843, 1 Apr 2004

  88. Carter MC, Alber DG, Baxter RC, Bithell SK, Budworth J, Chubb A, Cockerill GS, Dowdell VC, Henderson EA, Keegan SJ, Kelsey RD, Lockyer MJ, Stables JN, Wilson LJ, Powell KL (2006) 1,4-Benzodiazepines as inhibitors of respiratory syncytial virus. J Med Chem 49(7):2311–2319. doi:10.1021/jm051185t

    Article  CAS  Google Scholar 

  89. Henderson EA, Alber DG, Baxter RC, Bithell SK, Budworth J, Carter MC, Chubb A, Cockerill GS, Dowdell VC, Fraser IJ, Harris RA, Keegan SJ, Kelsey RD, Lumley JA, Stables JN, Weerasekera N, Wilson LJ, Powell KL (2007) 1,4-benzodiazepines as inhibitors of respiratory syncytial virus. The identification of a clinical candidate. J Med Chem 50(7):1685–1692. doi:10.1021/jm060747l

    Article  CAS  Google Scholar 

  90. Chapman J, Abbott E, Alber DG, Baxter RC, Bithell SK, Henderson EA, Carter MC, Chambers P, Chubb A, Cockerill GS, Collins PL, Dowdell VC, Keegan SJ, Kelsey RD, Lockyer MJ, Luongo C, Najarro P, Pickles RJ, Simmonds M, Taylor D, Tyms S, Wilson LJ, Powell KL (2007) RSV604, a novel inhibitor of respiratory syncytial virus replication. Antimicrob Agents Chemother 51(9):3346–3353. doi:10.1128/AAC.00211-07

    Article  CAS  Google Scholar 

  91. Chapman J, Cockerill GS (2011) Discovery and development of RSV604. In: Kazmierski WM (ed) Antiviral drugs: from basic discovery through clinical trials, 1st edn. Wiley Publishing, Hoboken

    Google Scholar 

  92. Challa S, Scott AD, Yuzhakov O, Zhou Y, Tiong-Yip CL, Gao N, Thresher J, Yu Q (2015) Mechanism of action for respiratory syncytial virus inhibitor RSV604. Antimicrob Agents Chemother 59(2):1080–1087. doi:10.1128/AAC.04119-14

    Article  Google Scholar 

  93. Ouizougun-Oubari M, Pereira N, Tarus B, Galloux M, Lassoued S, Fix J, Tortorici MA, Hoos S, Baron B, England P, Desmaele D, Couvreur P, Bontems F, Rey FA, Eleouet JF, Sizun C, Slama-Schwok A, Duquerroy S (2015) A druggable pocket at the nucleocapsid/phosphoprotein interaction site of human respiratory syncytial virus. J Virol 89(21):11129–11143. doi:10.1128/JVI.01612-15

    Article  CAS  Google Scholar 

  94. Yu Q (2015) Rsv polymerase and nucleoprotein inhibitors: Mechanism of action and resistance. Paper presented at the 4th isirv-AVG Conference, Austin, Texas, 2 June 2015

  95. Simoneau B, Bordeleau J, Fazal GL S, Mason S, Rancourt J (2005) RSV polymerase inhibitors. WO patent WO2005/042530. 12 May 2005

  96. Fearns R, Deval J (2016) New antiviral approaches for respiratory syncytial virus and other mononegaviruses: inhibiting the RNA polymerase. Antivir Res 134:63–76. doi:10.1016/j.antiviral.2016.08.006

    Article  CAS  Google Scholar 

  97. Mason SW, Lawetz C, Gaudette Y, Do F, Scouten E, Lagace L, Simoneau B, Liuzzi M (2004) Polyadenylation-dependent screening assay for respiratory syncytial virus RNA transcriptase activity and identification of an inhibitor. Nucleic Acids Res 32(16):4758–4767. doi:10.1093/nar/gkh809

    Article  CAS  Google Scholar 

  98. Liuzzi M, Mason SW, Cartier M, Lawetz C, McCollum RS, Dansereau N, Bolger G, Lapeyre N, Gaudette Y, Lagace L, Massariol MJ, Do F, Whitehead P, Lamarre L, Scouten E, Bordeleau J, Landry S, Rancourt J, Fazal G, Simoneau B (2005) Inhibitors of respiratory syncytial virus replication target cotranscriptional mRNA guanylylation by viral RNA-dependent RNA polymerase. J Virol 79(20):13105–13115. doi:10.1128/JVI.79.20.13105-13115.2005

    Article  CAS  Google Scholar 

  99. Sudo K, Miyazaki Y, Kojima N, Kobayashi M, Suzuki H, Shintani M, Shimizu Y (2005) YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action. Antivir Res 65(2):125–131. doi:10.1016/j.antiviral.2004.12.002

    Article  CAS  Google Scholar 

  100. Mackman RL, Sperandio D (2011) Anti-RSV compounds. WO patent WO2011/005842, 13 Jan 2011

  101. Xiong H, Foulk M, Aschenbrenner L, Fan J, Tiong-Yip CL, Johnson KD, Moustakas D, Fleming PR, Brown DG, Zhang M, Ferguson D, Wu D, Yu Q (2013) Discovery of a potent respiratory syncytial virus RNA polymerase inhibitor. Bioorg Med Chem Lett 23(24):6789–6793. doi:10.1016/j.bmcl.2013.10.018

    Article  CAS  Google Scholar 

  102. Tiong-Yip CL, Aschenbrenner L, Johnson KD, McLaughlin RE, Fan J, Challa S, Xiong H, Yu Q (2014) Characterization of a respiratory syncytial virus L protein inhibitor. Antimicrob Agents Chemother 58(7):3867–3873. doi:10.1128/AAC.02540-14

    Article  Google Scholar 

  103. Hunt SF, Onions ST, Sherbukhin V, Fordyce EAF, Murray PJ, Coates MS, Brookes DW, Ito K, Strong P (2016) Preparation of novel 5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine derivatives for treating respiratory syncytial virus (RSV) infection. WO patent WO2016/055792, 14 Apr 2016

  104. Hunt SF, Onions ST, Sherbukhin V, Fordyce EAF, Murray PJ, Brookes DW, Ito K, Strong P (2016) Preparation of novel 5,6-dihydro-4H-benzo[b]thieno-[2,3-d]azepine derivative for treating RSV infection. WO patent WO2016/055791, 14 Apr 2016

  105. Fordyce EAF, Hunt SF, Onions ST, Sherbukhin V, Coates MS, Brookes DW, Ito K, Strong P, King-Underwood J (2016) Preparation of novel 4,5-dihydro-6H-thieno[3,2-d]benzazepine derivatives for treating respiratory syncytial virus (RSV) infection. WO patent WO2016/097761, 23 June 2016

  106. Wang G, Smith DB, Beigelman L, Deval J, Prhavc M (2013) Preparation of substituted nucleosides, nucleotides and analogs thereof as antiviral agents. WO patent WO2013/142525, 26 Sep 2013

  107. Beigelman L, Wang G, Smith DB, Deval J, Prhavc M (2013) Preparation of amino acid-substituted nucleosides, nucleotides and analogs as antiviral agents. WO patent WO2013/096679, 27 June 2013

  108. Wang G, Deval J, Hong J, Dyatkina N, Prhavc M, Taylor J, Fung A, Jin Z, Stevens SK, Serebryany V, Liu J, Zhang Q, Tam Y, Chanda SM, Smith DB, Symons JA, Blatt LM, Beigelman L (2015) Discovery of 4′-chloromethyl-2′-deoxy-3′,5′-di-O-isobutyryl-2′-fluorocytidine (ALS-8176), a first-in-class RSV polymerase inhibitor for treatment of human respiratory syncytial virus infection. J Med Chem 58(4):1862–1878. doi:10.1021/jm5017279

    Article  CAS  Google Scholar 

  109. Clarke MO, Mackman R, Byun D, Hui H, Barauskas O, Birkus G, Chun BK, Doerffler E, Feng J, Karki K, Lee G, Perron M, Siegel D, Swaminathan S, Lee W (2015) Discovery of beta-D-2′-deoxy-2′-alpha-fluoro-4′-alpha-cyano-5-aza-7,9-dideaza adenosine as a potent nucleoside inhibitor of respiratory syncytial virus with excellent selectivity over mitochondrial RNA and DNA polymerases. Bioorg Med Chem Lett 25(12):2484–2487. doi:10.1016/j.bmcl.2015.04.073

    Article  CAS  Google Scholar 

  110. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen SS, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S (2016) Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531(7594):381–385. doi:10.1038/nature17180

    Article  CAS  Google Scholar 

  111. Hardy RW, Wertz GW (1998) The product of the respiratory syncytial virus M2 gene ORF1 enhances readthrough of intergenic junctions during viral transcription. J Virol 72(1):520–526

    CAS  Google Scholar 

  112. Tran TL, Castagne N, Dubosclard V, Noinville S, Koch E, Moudjou M, Henry C, Bernard J, Yeo RP, Eleouet JF (2009) The respiratory syncytial virus M2-1 protein forms tetramers and interacts with RNA and P in a competitive manner. J Virol 83(13):6363–6374. doi:10.1128/JVI.00335-09

    Article  CAS  Google Scholar 

  113. Hardy RW, Wertz GW (2000) The Cys(3)-His(1) motif of the respiratory syncytial virus M2-1 protein is essential for protein function. J Virol 74(13):5880–5885

    Article  CAS  Google Scholar 

  114. Boukhvalova MS, Prince GA, Blanco JC (2010) Inactivation of respiratory syncytial virus by zinc finger reactive compounds. Virol J 7:20. doi:10.1186/1743-422X-7-20

    Article  Google Scholar 

  115. Tanner SJ, Ariza A, Richard CA, Kyle HF, Dods RL, Blondot ML, Wu W, Trincao J, Trinh CH, Hiscox JA, Carroll MW, Silman NJ, Eleouet JF, Edwards TA, Barr JN (2014) Crystal structure of the essential transcription antiterminator M2-1 protein of human respiratory syncytial virus and implications of its phosphorylation. Proc Natl Acad Sci USA 111(4):1580–1585. doi:10.1073/pnas.1317262111

    Article  CAS  Google Scholar 

  116. Cancellieri M, Bassetto M, Widjaja I, van Kuppeveld F, de Haan CA, Brancale A (2015) In silico structure-based design and synthesis of novel anti-RSV compounds. Antivir Res 122:46–50. doi:10.1016/j.antiviral.2015.08.003

    Article  CAS  Google Scholar 

  117. Bailly B, Richard CA, Sharma G, Wang L, Johansen L, Cao J, Pendharkar V, Sharma DC, Galloux M, Wang Y, Cui R, Zou G, Guillon P, von Itzstein M, Eleouet JF, Altmeyer R (2016) Targeting human respiratory syncytial virus transcription anti-termination factor M2-1 to inhibit in vivo viral replication. Sci Rep 6:25806. doi:10.1038/srep25806

    Article  CAS  Google Scholar 

  118. Noah JW, Severson WE, Chung DH, Moore B, Jia F, Xu X, Maddox C, Rasmussen L, Sosa MI, Tower NA, Ananthan S, Evans CW, White EL, Jonsson C, Matharu DS, Flaherty DP, Simpson DS, Golden JE, Aube J (2010) Identification of a series of quinazolinediones as potent, selective, post-entry inhibitors of human respiratory syncytial virus (hRSV) via a cell-based high throughput screen and chemical optimization. In: Probe Reports from the NIH Molecular Libraries Program. National Center for Biotechnology Information (US), Bethesda, MD. Available from: https://www.ncbi.nlm.nih.gov/books/NBK133445/

  119. Matharu DS, Flaherty DP, Simpson DS, Schroeder CE, Chung D, Yan D, Noah JW, Jonsson CB, White EL, Aube J, Plemper RK, Severson WE, Golden JE (2014) Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity. J Med Chem 57(24):10314–10328. doi:10.1021/jm500902x

    Article  CAS  Google Scholar 

  120. Evans CW, Atkins C, Pathak A, Gilbert BE, Noah JW (2015) Benzimidazole analogs inhibit respiratory syncytial virus G protein function. Antivir Res 121:31–38. doi:10.1016/j.antiviral.2015.06.016

    Article  CAS  Google Scholar 

  121. Laganas VA, Dunn EF, McLaughlin RE, Tiong-Yip CL, Yuzhakov O, Isabella VM, Hill P, Yu Q (2015) Characterization of novel respiratory syncytial virus inhibitors identified by high throughput screen. Antivir Res 115:71–74. doi:10.1016/j.antiviral.2014.12.012

    Article  CAS  Google Scholar 

  122. Wang G, Beigelman L, Truong A, Napolitano C, Andreotti D, He H, Stein KA (2015) Preparation of carboxamide derivatives as antiviral compounds. WO patent WO2015/026792. 26 Feb 2015

  123. Alvarez R, Elbashir S, Borland T, Toudjarska I, Hadwiger P, John M, Roehl I, Morskaya SS, Martinello R, Kahn J, Van Ranst M, Tripp RA, DeVincenzo JP, Pandey R, Maier M, Nechev L, Manoharan M, Kotelianski V, Meyers R (2009) RNA interference-mediated silencing of the respiratory syncytial virus nucleocapsid defines a potent antiviral strategy. Antimicrob Agents Chemother 53(9):3952–3962. doi:10.1128/AAC.00014-09

    Article  CAS  Google Scholar 

  124. DeVincenzo J, Lambkin-Williams R, Wilkinson T, Cehelsky J, Nochur S, Walsh E, Meyers R, Gollob J, Vaishnaw A (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci USA 107(19):8800–8805. doi:10.1073/pnas.0912186107

    Article  CAS  Google Scholar 

  125. Mills JT, Van Kirk JE, Wright PF, Chanock RM (1971) Experimental respiratory syncytial virus infection of adults. Possible mechanisms of resistance to infection and illness. J Immunol 107(1):123–130

    Google Scholar 

  126. Higgins PG, Barrow GI, Tyrrell DA, Isaacs D, Gauci CL (1990) The efficacy of intranasal interferon alpha-2a in respiratory syncytial virus infection in volunteers. Antivir Res 14(1):3–10

    Article  CAS  Google Scholar 

  127. DeVincenzo JP, El Saleeby CM, Bush AJ (2005) Respiratory syncytial virus load predicts disease severity in previously healthy infants. J Infect Dis 191(11):1861–1868. doi:10.1086/430008

    Article  Google Scholar 

  128. Perkins SM, Webb DL, Torrance SA, El Saleeby C, Harrison LM, Aitken JA, Patel A, DeVincenzo JP (2005) Comparison of a real-time reverse transcriptase PCR assay and a culture technique for quantitative assessment of viral load in children naturally infected with respiratory syncytial virus. J Clin Microbiol 43(5):2356–2362. doi:10.1128/JCM.43.5.2356-2362.2005

    Article  CAS  Google Scholar 

  129. Yan D, Lee S, Thakkar VD, Luo M, Moore ML, Plemper RK (2014) Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors. Proc Natl Acad Sci USA 111(33):E3441–3449. doi:10.1073/pnas.1405198111

    Article  CAS  Google Scholar 

  130. Eisenberg EJ, Wang WK, Carey A, Gershwin L, Perron M, Mackman R (2015) Presatovir (GS-5806), a novel fusion inhibitor of respiratory syncytial virus, delivers high respiratory tract levels in nonclinical species. Paper presented at the IDWeek 2015, San Diego, California, 7–11 October 2015

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Correspondence to Kai Lin.

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This article is part of the Topical Collection “Antiviral Drug Research”; edited by Guangxin Liang and Zheng Yin.

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Shook, B.C., Lin, K. Recent Advances in Developing Antiviral Therapies for Respiratory Syncytial Virus. Top Curr Chem (Z) 375, 40 (2017). https://doi.org/10.1007/s41061-017-0129-4

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