1887

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Volume 102, Issue 8

Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A No Access

Abstract

Human respiratory syncytial virus (hRSV) is a major cause of respiratory illness in young children and can cause severe infections in the elderly or in immunocompromised adults. To date, there is no vaccine to prevent hRSV infections, and disease management is limited to preventive care by palivizumab in infants and supportive care for adults. Intervention with small-molecule antivirals specific for hRSV represents a good alternative, but no such compounds are currently approved. The investigation of existing drugs for new therapeutic purposes (drug repositioning) can be a faster approach to address this issue. In this study, we show that chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A (long strain) and synergistically increase the anti-replicative effect of ribavirin . Moreover, chloroquine, but not pyrimethamine, inhibits hRSV replication in the mouse model. Our results show that chloroquine can potentially be an interesting compound for treatment of hRSV infection in monotherapy or in combination with other antivirals.

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Keyword(s): chloroquine , drug combination , pneumovirus , pyrimethamine , respiratory syncytial virus and ribavirin
© 2021 The Authors
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2021-08-03
2024-04-27
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References

  1. Lee W-J, Kim D-W, Lee HS, Lee HY et al. Complete genome sequence of human respiratory syncytial virus genotype a with a 72-nucleotide duplication in the attachment protein G gene. J Virol 2012; 86:13810–13811 [View Article]
     [Google Scholar]
  2. Falsey AR, Walsh EE. Respiratory syncytial virus infection in elderly adults. Drugs Aging 2005; 22:577–587 [View Article]
     [Google Scholar]
  3. Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev 2000; 13:371–384 [View Article]
     [Google Scholar]
  4. Lee N, Lui GC, Wong KT, TC L, Tse EC et al. High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections. Clin Infect Dis 2013; 57:1069–1077 [View Article]
     [Google Scholar]
  5. Englund JA, Sullivan CJ, Jordan MC, Dehner LP, Vercellotti GM et al. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med 1988; 109:203–208 [View Article]
     [Google Scholar]
  6. Nam HH, Ison MG. Respiratory syncytial virus infection in adults. BMJ 2019; 366:l5021 [View Article]
     [Google Scholar]
  7. National Institute of Allergy and Infectious Diseases Respiratory syncytial virus (RSV; 2019 https://www.niaid.nih.gov/diseases-conditions/respiratory-syncytial-virus-rsv
  8. Broadbent L, Groves H, Shields MD, Power UF. Respiratory syncytial virus, an ongoing medical dilemma: an expert commentary on respiratory syncytial virus prophylactic and therapeutic pharmaceuticals currently in clinical trials. Influenza Other Respir Viruses 2015; 9:169–178 [View Article]
     [Google Scholar]
  9. Hall CB, Walsh EE, Hruska JF, Betts RF, Hall WJ. Ribavirin treatment of experimental respiratory syncytial viral infection. A controlled double blind study in young adults. JAMA 1983; 249:2666–2670 [View Article]
     [Google Scholar]
  10. Taber LH, Knight V, Gilbert BE, Mc Clung HW, Wilson SZ. Ribavirin aerosol treatment of bronchiolitis associated with respiratory syncytial virus infection in infants. Pediatrics 1983; 72:613–618 [PubMed]
     [Google Scholar]
  11. Randolph AG, Wang EE. Ribavirin for respiratory syncytial virus lower respiratory tract infection. Asystematic overview Arch Pediatr Adolesc Med 1996; 150:942–947
     [Google Scholar]
  12. Ghosh S, Champlin RE, Englund J, Giralt SA, Rolston K et al. Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin. Bone Marrow Transplant 2000; 25:751–755 [View Article]
     [Google Scholar]
  13. Mc Carthy AJ, Kingman HM, Kelly C, Taylor GS, Caul EO et al. The outcome of 26 patients with respiratory syncytial virus infection following allogeneic stemcell transplantation. Bone Marrow Transplant 1999; 24:1315–1322 [View Article]
     [Google Scholar]
  14. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood 2011; 117:2755–2763 [View Article]
     [Google Scholar]
  15. Chemaly RF, Shah DP, Boeckh MJ. Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies. ClinInfect Dis 2014; 59:344–351 [View Article]
     [Google Scholar]
  16. De Vincenzo JP, Whitley RJ, Mackman RL, Scaglioni-Weinlich C, Harrison L et al. Oral GS-5806 activity in a respiratory syncytial virus challenge study. N Engl J Med 2014; 371:711–722 [View Article]
     [Google Scholar]
  17. Stevens M, Rusch S, DeVincenzo J, Kim Y-I, Harrison L et al. Antiviral activity of oral JNJ-53718678 in healthy adult volunteers challenged with respiratory syncytial virus: A Placebo-controlled study. J Infect Dis 2018; 218:748–756 [View Article]
     [Google Scholar]
  18. De Vicenzo T, Tait D, Oluwayi O, Mori J, Thomas E et al. Safety and Efficacy of Oral RV521 in a Human Respiratory Syncytial Virus (RSV) Phase 2a Challenge Study. Am J Respir Crit Care Med 2018; 197:A7715
     [Google Scholar]
  19. Kim YI, Pareek R, Murphy R, Harrison L, Farrell E et al. The antiviral effects of RSV fusion inhibitor, MDT-637, on clinical isolates, vs its achievable concentrations in the human respiratory tract and comparison to ribavirin. Influenza Other Respir Viruses 2017; 11:525–530 [View Article]
     [Google Scholar]
  20. Gottlieb J, Torres F, Haddad T, Dhillon G, Dilling DF et al. A Phase 2b Randomized Controlled Trial of Presatovir, an Oral RSV Fusion Inhibitor, for the Treatment of Respiratory Syncytial Virus (RSV) in Lung Transplant (LT) Recipients. J Heart Lung Transplant 2018; 37:S155 [View Article]
     [Google Scholar]
  21. De Vincenzo JP, Mc Clure MW, Symons JA, Fathi H, Westland CN et al. Activity of Oral ALS-008176 in a respiratory syncytial virus challenge study. Engl J Med 2015; 373:2048–2058 [View Article]
     [Google Scholar]
  22. Patel K, Kirkpatrick CM, Nieforth KA, Chanda S, Zhang Q et al. Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans. J Antimicrob Chemother 2019; 74:442–452 [View Article]
     [Google Scholar]
  23. Beigel JH, Nam HH, Adams PL, Krafft A, Ince WL et al. Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res 2019; 167:45–67 [View Article]
     [Google Scholar]
  24. Challa S, Scott AD, Yuzhakov O, Zhou Y, Tiong-Yip CL et al. Mechanism of action for respiratory syncytial virus inhibitor RSV604. Antimicrob Agents Chemother 2015; 59:1080–1087 [View Article]
     [Google Scholar]
  25. Simões EAF, DeVincenzo JP, Boeckh M, Bont L, Crowe JE et al. Challenges and opportunities in developing respiratory syncytial virus therapeutics. J Infect Dis 2015; 211 Suppl 1:S1–S20 [View Article]
     [Google Scholar]
  26. Simon A, Karsten V, Cehelsky J, Shah S, Bettencourt B et al. Results of a phase 2b multicenter trial of ALN-RSV01 in respiratory syncytial virus (RSV)- infected lung transplant patients. Eur Respir J 2012; 40:1476
     [Google Scholar]
  27. Domachowske JB, Khan AA, Esser MT, Jensen K, Takas T et al. Safety, tolerability and pharmacokinetics of MEDI8897, an extended half-life single-dose respiratory syncytial virus prefusion F-targeting monoclonal antibody administered as a single dose to healthy preterm infants. Pediatr Infect Dis J 2018; 37:886–892 [View Article]
     [Google Scholar]
  28. Larios Mora A, Detalle L, Gallup JM, Van Geelen A, Stohr T et al. Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs. MAbs 2018; 10:778–795 [View Article]
     [Google Scholar]
  29. Collins PL, Melero JA. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Res 2011; 162:80–99 [View Article]
     [Google Scholar]
  30. Pekosz A, Glass GE. Emerging viral diseases. Md Med 2008; 9:11–16 [PubMed]
     [Google Scholar]
  31. Keyaerts E, Vijgen L, Maes P, Neyts J, Ranst MV. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323:264–268 [View Article]
     [Google Scholar]
  32. Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother 2009; 53:3416–3421 [View Article]
     [Google Scholar]
  33. Tan YW, Yam WK, Sun J, Chu JJH. An evaluation of chloroquine as a broad-acting antiviral against hand, foot and mouth disease. Antiviral Res 2018; 149:143–149 [View Article]
     [Google Scholar]
  34. Li C, Zhu X, Ji X, Quanquin N, Deng YQ et al. Chloroquine, a FDA-approved drug, prevents Zika virus infection and its associated congenital microcephaly in mice. Ebio Medicine 2017; 24:189–194 [View Article]
     [Google Scholar]
  35. Yan Y, Zou Z, Sun Y, Li X, KF X et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res 2013; 23:300–302 [View Article]
     [Google Scholar]
  36. Rogée S, Larrous F, Jochmans D, Ben-Khalifa Y, Neyts J et al. Pyrimethamine inhibits rabies virus replication in vitro. Antiviral Res 2019; 161:1–9 [View Article]
     [Google Scholar]
  37. Oguariri RM, Adelsberger JW, Baseler MW, Imamichi T. Evaluation of the effect of pyrimethamine, an anti-malarial drug, on HIV-1 replication. Virus Res 2010; 153:269–276 [View Article]
     [Google Scholar]
  38. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res 2020; 177:104762 [View Article]
     [Google Scholar]
  39. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949: [View Article]
     [Google Scholar]
  40. Gasmi A, Peana M, Noor S, Lysiuk R, Menzel A et al. Chloroquine and hydroxychloroquine in the treatment of COVID-19: the never-ending story. Appl Microbiol Biotechnol 2021; 105:1333–1343 [View Article]
     [Google Scholar]
  41. Castagné N, Barbier A, Bernard J, Rezaei H, Huet JC et al. Biochemical characterization of the respiratory syncytial virus P-P and P-N protein complexes and localization of the P protein oligomerization domain. J Gen Virol 2004; 85:1643–1653 [View Article]
     [Google Scholar]
  42. Rameix-Welti MA, Le Goffic R, Hervé PL, Sourimant J, Rémot A et al. Visualizing the replication of respiratory syncytial virus in cells and in living mice. Nat Commun 2014; 5:5104 [View Article]
     [Google Scholar]
  43. Buchholz UJ, Finke S, Conzelmann KK. Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter. J Virol 1999; 73:251–259 [View Article] [PubMed]
     [Google Scholar]
  44. Esneau C, Raynal B, Roblin P, Brûlé S, Richard CA et al. Biochemical characterization of the respiratory syncytial virus N0-P complex in solution. J Biol Chem 2019; 294:3647–3660 [View Article]
     [Google Scholar]
  45. Richard CA, Rincheval V, Lassoued S, Fix J, Cardone C et al. RSV hijacks cellular protein phosphatase 1 to regulate M2-1 phosphorylation and viral transcription. PLoS Pathog 2018; 14:e1006920 [View Article]
     [Google Scholar]
  46. Tcherniuk SO, Oleinikov AV. Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295. Cancer Lett 2015; 361:97–103 [View Article]
     [Google Scholar]
  47. Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006; 58:621–681 [View Article]
     [Google Scholar]
  48. Sertkaya A, Birkenbach A, Berlind A, Eyraud J. Examination of Clinical Trial Costs and Barriers for Drug Development US Department of health and human services, office of the assistant secretary for planning and evaluation report; 2014 pp 1–92
     [Google Scholar]
  49. Xue H, Li J, Xie H, Wang Y. Review of drug repositioning approaches and resources. Int J Biol Sci 2018; 14:1232–1244 [View Article]
     [Google Scholar]
  50. Cai Q, Yang M, Liu D, Chen J, Shu D et al. Experimental treatment with favipiravir for COVID-19: An open-label control study. Engineering (Beijing) 2020; 6:1192–1198 [View Article]
     [Google Scholar]
  51. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19. Drug Discov Ther 2020; 14:58–60 [View Article]
     [Google Scholar]
  52. Wu R, Wang L, Kuo HD, Shannar A, Peter R et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep 20201–15 [View Article]
     [Google Scholar]
  53. Duan Y, Zhu HL, Zhou C. Advance of promising targets and agents against COVID-19 in China. Drug Discov Today 2020; 25:810–812 [View Article]
     [Google Scholar]
  54. Lythgoe MP, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Trends Pharmacol Sci 2020; 41:363–382 [View Article]
     [Google Scholar]
  55. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS et al. Remdesivir for the treatment of Covid-19 - preliminary report. N Engl J Med 2020; 383:1813–1826 [View Article]
     [Google Scholar]
  56. Zhang Z, Wang S, Tu X, Peng X, Huang Y et al. A comparative study on the time to achieve negative nucleic acid testing and hospital stays between Danoprevir and Lopinavir/Ritonavir in the treatment of patients with COVID-19. J Med Virol 2020; 92:2631–2636 [View Article]
     [Google Scholar]
  57. Savarino A, Gennero L, Sperber K, Boelaert JR. The anti-HIV-1 activity of chloroquine. J Clin Virol 2001; 20:131–135 [View Article]
     [Google Scholar]
  58. Superti F, Seganti L, Orsi W, Divizia M, Gabrieli R et al. The effect of lipophilic amines on the growth of hepatitis A virus in Frp/3 cells. Arch Virol 1987; 96:289–296 [View Article]
     [Google Scholar]
  59. Kouroumalis EA, Koskinas J. Treatment of chronic active hepatitis B (CAH B) with chloroquine: a preliminary report. Ann Acad Med Singap 1986; 15:149–152 [PubMed]
     [Google Scholar]
  60. Mizui T, Yamashina S, Tanida I, Takei Y, Ueno T et al. Inhibition of hepatitis C virus replication by chloroquine targeting virus-associated autophagy. J Gastroenterol 2010; 45:195–203 [View Article]
     [Google Scholar]
  61. Ooi EE, Chew JS, Loh JP, Chua RC. In vitro inhibition of human influenza A virus replication by chloroquine. Virol J 2006; 3:39 [View Article]
     [Google Scholar]
  62. Shibata M, Aoki H, Tsurumi T, Sugiura Y, Nishiyama Y et al. Mechanism of uncoating of influenza B virus in MDCK cells: action of chloroquine. J Gen Virol 1983; 64:1149–1156 [View Article]
     [Google Scholar]
  63. Delogu I, Lamballerie de. Chikungunya disease and chloroquine treatment. J Med Virol 2011; 83:1058–1059 [View Article]
     [Google Scholar]
  64. Farias KJ, Machado PR, de Almeida Junior RF, de Aquino AA, da Fonseca BA. Chloroquine interferes with dengue-2 virus replication in U937 cells. Microbiol Immunol 2014; 58:318–326 [View Article]
     [Google Scholar]
  65. Delvecchio R, Higa LM, Pezzuto P, Valadão AL, Garcez PP et al. Chloroquine, an endocytosis blocking agent, inhibits Zika virus infection in different cell models. Viruses 2016; 8:322 [View Article]
     [Google Scholar]
  66. Glushakova SE, Lukashevich IS. Early events in arenavirus replication are sensitive to lysosomotropic compounds. Arch Virol 1989; 104:157–161 [View Article] [PubMed]
     [Google Scholar]
  67. Porotto M, Orefice G, Yokoyama CC, Mungall BA, Realubit R. Simulating Henipavirus multicycle replication in a screening assay leads to identification of a promising candidate for therapy. J Virol 2009; 83:5148–5155 [View Article] [PubMed]
     [Google Scholar]
  68. Freiberg AN, Worthy MN, Lee B, Holbrook MR. Combined chloroquine and ribavirin treatment does not prevent death in a hamster model of Nipah and Hendra virus infection. J Gen Virol 2010; 91:765–772 [View Article]
     [Google Scholar]
  69. Ferraris O, Moroso M, Pernet O, Emonet S, Ferrier Rembert A et al. Evaluation of Crimean–Congo hemorrhagic fever virus in vitro inhibition by chloroquine and chlorpromazine, two FDA approved molecules. Antiviral Res 2015; 118:75–81 [View Article]
     [Google Scholar]
  70. Dowall SD, Bosworth A, Watson R, Bewley K, Taylor I. Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model. J Gen Virol 2015; 96:3484–3492 [View Article] [PubMed]
     [Google Scholar]
  71. Koyama AH, Uchida T. Inhibition of multiplication of herpes simplex virus type 1 by ammonium chloride and chloroquine. Virology 1984; 138:332–335 [View Article] [PubMed]
     [Google Scholar]
  72. Million M, Lagier JC, Gautret P, Colson P, Fournier PE et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med Infect Dis 2020101738 [View Article]
     [Google Scholar]
  73. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020105949 [View Article]
     [Google Scholar]
  74. Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun 2004; 323:264–268 [View Article]
     [Google Scholar]
  75. de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother 2014; 58:4875–4884 [View Article]
     [Google Scholar]
  76. Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases?. Lancet Infect Dis 2003; 3:722–727 [View Article]
     [Google Scholar]
  77. Liu H, Qin Y, Zhai D, Zhang Q, Gu J et al. Antimalarial drug pyrimethamine plays a dual role in antitumor proliferation and metastasis through targeting DHFR and TP. Mol Cancer Ther 2019; 18:541 [View Article]
     [Google Scholar]
  78. Zhou X, Zhang J, Hu X, He P, Guo J et al. Pyrimethamine elicits antitumor effects on prostate cancer by inhibiting the p38-NF-κB Pathway. Front Pharmacol 2020; 11:758 [View Article]
     [Google Scholar]
  79. Takakura A, Nelson EA, Haque N, Humphreys BD, Zandi-Nejad K et al. Pyrimethamine inhibits adult polycystic kidney disease by modulating stat signaling pathways. Hum Mol Genet 2011; 20:4143–4154 [View Article]
     [Google Scholar]
  80. Heppler LN, Walker SR, Attarha S, Page BD, Frank DA. Pyrimethamine Inhibits STAT3 Transcriptional Activity Via Dihydrofolate Reductase. Proceedings of the American Association for Cancer Research Annual Meeting 2019 Atlanta, GA. Philadelphia (PA): AACR; Cancer Res; 2019
     [Google Scholar]
  81. Tcherniuk SO, Chesnokova O, Oleinikov IV, Oleinikov AV. Nicotinamide inhibits the growth of P. falciparum and enhances the antimalarial effect of artemisinin, chloroquine and pyrimethamine. Mol Biochem Parasitol 2017; 216:14–20 [View Article]
     [Google Scholar]
  82. Sidwell RW, Arnett G, Schabel FM. In vitro effect of a variety of biologically active compounds on human cytomegalovirus. Chemotherapy 1972; 17:259–282 [View Article] [PubMed]
     [Google Scholar]
  83. Cameron CE, Castro C. The mechanism of action of ribavirin: lethal mutagenesis of RNA virus genomes mediated by the viral RNA-dependent RNA polymerase. Curr Opin Infect Dis 2001; 14:757–764 [View Article]
     [Google Scholar]
  84. Brillanti S, Garson J, Foli M. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon alfa-resistant chronic hepatitis C. Gastroenterology 1994; 107:812–817 [View Article] [PubMed]
     [Google Scholar]
  85. Kentsis A, Topisirovic I, Culjkovic B, Shao L, Borden KL. Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap. Proc Natl Acad Sci USA 2004; 101:18105–18110 [View Article]
     [Google Scholar]
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Chloroquine and pyrimethamine inhibit the replication of human respiratory syncytial virus A
J. Gen. Virol. 102, 001627 (2021); https://doi.org/10.1099/jgv.0.001627
/content/journal/jgv/10.1099/jgv.0.001627
/content/journal/jgv/10.1099/jgv.0.001627
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