1887

Journal of Medical Microbiology logo

Volume 66, Issue 9

A review of candidate therapies for Middle East respiratory syndrome from a molecular perspective Free

Abstract

There have been 2040 laboratory-confirmed cases of Middle East respiratory syndrome coronavirus (MERS-CoV) in 27 countries, with a mortality rate of 34.9 %. There is no specific therapy. The current therapies have mainly been adapted from severe acute respiratory syndrome (SARS-CoV) treatments, including broad-spectrum antibiotics, corticosteroids, interferons, ribavirin, lopinavir–ritonavir or mycophenolate mofetil, and have not been subject to well-organized clinical trials. The development of specific therapies and vaccines is therefore urgently required. We examine existing and potential therapies and vaccines from a molecular perspective. These include viral S protein targeting; inhibitors of host proteases, including TMPRSS2, cathepsin L and furin protease, and of viral M(pro) and the PL(pro) proteases; convalescent plasma; and vaccine candidates. The Medline database was searched using combinations and variations of terms, including ‘Middle East respiratory syndrome coronavirus’, ‘MERS-CoV’, ‘SARS’, ‘therapy’, ‘molecular’, ‘vaccine’, ‘prophylactic’, ‘S protein’, ‘DPP4’, ‘heptad repeat’, ‘protease’, ‘inhibitor’, ‘anti-viral’, ‘broad-spectrum’, ‘interferon’, ‘convalescent plasma’, ‘lopinavir ritonavir’, ‘antibodies’, ‘antiviral peptides’ and ‘live attenuated viruses’. There are many options for the development of MERS-CoV-specific therapies. Currently, MERS-CoV is not considered to have pandemic potential. However, the high mortality rate and potential for mutations that could increase transmissibility give urgency to the search for direct, effective therapies. Well-designed and controlled clinical trials are needed, both for existing therapies and for prospective direct therapies.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Antiviral peptide , camostat , convalescent plasma , DPP4 , GLS-5300 , glycopeptide antibiotic , interferon , lopinavir , M(pro) , MERS-CoV , monoclonal antibodies , PL(pro) , protease , S protein and vaccine
© 2017 The Authors
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000565
2017-09-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/jmm/66/9/1261.html?itemId=/content/journal/jmm/10.1099/jmm.0.000565&mimeType=html&fmt=ahah

References

  1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012; 367:1814–1820 [View Article][PubMed]
     [Google Scholar]
  2. WHO Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [Internet] Geneva: World Health Organization (WHO); 2017 www.who.int/emergencies/mers-cov/en/ Cited 11 July 2017
    [Google Scholar]
  3. Drexler JF, Corman VM, Drosten C. Ecology, evolution and classification of bat coronaviruses in the aftermath of SARS. Antiviral Res 2014; 101:45–56 [View Article][PubMed]
     [Google Scholar]
  4. Haagmans BL, Al Dhahiry SH, Reusken CB, Raj VS, Galiano M et al. Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation. Lancet Infect Dis 2014; 14:140–145 [View Article][PubMed]
     [Google Scholar]
  5. Reusken CB, Haagmans BL, Müller MA, Gutierrez C, Godeke GJ et al. Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. Lancet Infect Dis 2013; 13:859–866 [View Article][PubMed]
     [Google Scholar]
  6. Hijawi B, Abdallat M, Sayaydeh A, Alqasrawi S, Haddadin A et al. Novel coronavirus infections in Jordan, April 2012: epidemiological findings from a retrospective investigation/Infections par le nouveau coronavirus en Jordanie, avril 2012: résultats épidémiologiques d'une étude rétrospective. East Mediterr Health J 2013; 19:S12–S18
     [Google Scholar]
  7. Assiri A, McGeer A, Perl TM, Price CS, Al Rabeeah AA et al. Hospital outbreak of Middle East respiratory syndrome coronavirus. N Engl J Med 2013; 369:407–416 [View Article][PubMed]
     [Google Scholar]
  8. Oboho IK, Tomczyk SM, Al-Asmari AM, Banjar AA, Al-Mugti H et al. 2014 MERS-CoV outbreak in Jeddah – a link to health care facilities. N Engl J Med 2015; 372:846–854 [View Article][PubMed]
     [Google Scholar]
  9. Fagbo SF, Skakni L, Chu DK, Garbati MA, Joseph M et al. Molecular epidemiology of hospital outbreak of Middle East respiratory syndrome, Riyadh, Saudi Arabia, 2014. Emerg Infect Dis 2015 1981; 21:1981–1988 [View Article][PubMed]
     [Google Scholar]
  10. Drosten C, Muth D, Corman VM, Hussain R, Al Masri M et al. An observational, laboratory-based study of outbreaks of middle East respiratory syndrome coronavirus in Jeddah and Riyadh, Kingdom of Saudi Arabia, 2014. Clin Infect Dis 2015; 60:369–377 [View Article][PubMed]
     [Google Scholar]
  11. Almekhlafi GA, Albarrak MM, Mandourah Y, Hassan S, Alwan A et al. Presentation and outcome of Middle East respiratory syndrome in Saudi intensive care unit patients. Crit Care 2016; 20:123 [View Article][PubMed]
     [Google Scholar]
  12. Balkhy HH, Alenazi TH, Alshamrani MM, Baffoe-Bonnie H, Al-Abdely HM et al. Notes from the field: nosocomial outbreak of Middle East respiratory syndrome in a large Tertiary Care Hospital - Riyadh, Saudi Arabia, 2015. MMWR Morb Mortal Wkly Rep 2016; 65:163–164 [View Article][PubMed]
     [Google Scholar]
  13. Balkhy HH, Perl TM, Arabi YM. Preventing healthcare-associated transmission of the Middle East respiratory syndrome (MERS): our Achilles heel. J Infect Public Health 2016; 9:208–212 [View Article][PubMed]
     [Google Scholar]
  14. World Health Organization (WHO 2017; Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV in Republic of Korea at a glance. www.wpro.who.int/outbreaks_emergencies/wpro_coronavirus/en/ Accessed 10 January 2017
  15. World Health Organization (WHO) 2015; Middle East respiratory syndrome coronavirus (MERS-CoV): Summary of Current Situation, Literature Update and Risk Assessment. www.who.int/csr/disease/coronavirus_infections/risk-assessment-7july2015/en/ Accessed 10 January 2017
  16. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S et al. Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis 2013; 13:752–761 [View Article][PubMed]
     [Google Scholar]
  17. Min CK, Cheon S, Ha NY, Sohn KM, Kim Y et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep 2016; 6:25359 [View Article][PubMed]
     [Google Scholar]
  18. Wang Y, Liu D, Shi W, Lu R, Wang W et al. Origin and possible genetic recombination of the Middle East respiratory syndrome coronavirus from the first imported case in China: phylogenetics and coalescence analysis. MBio 2015; 6:e01280-15 [View Article][PubMed]
     [Google Scholar]
  19. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen KY. Coronaviruses – drug discovery and therapeutic options. Nat Rev Drug Discov 2016; 15:327–347 [View Article][PubMed]
     [Google Scholar]
  20. Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013; 495:251–254 [View Article][PubMed]
     [Google Scholar]
  21. Wang N, Shi X, Jiang L, Zhang S, Wang D et al. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res 2013; 23:986–993 [View Article][PubMed]
     [Google Scholar]
  22. Mo Y, Fisher D. A review of treatment modalities for Middle East respiratory syndrome. J Antimicrob Chemother 2016; 71:3340–3350 [View Article][PubMed]
     [Google Scholar]
  23. Shirato K, Kawase M, Matsuyama S. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol 2013; 87:12552–12561 [View Article][PubMed]
     [Google Scholar]
  24. Müller MA, Raj VS, Muth D, Meyer B, Kallies S et al. Human coronavirus EMC does not require the SARS-coronavirus receptor and maintains broad replicative capability in mammalian cell lines. mBio 2012; 3:e00515-12 [View Article][PubMed]
     [Google Scholar]
  25. Chan RW, Hemida MG, Kayali G, Chu DK, Poon LL et al. Tropism and replication of Middle East respiratory syndrome coronavirus from dromedary camels in the human respiratory tract: an in-vitro and ex-vivo study. Lancet Respir Med 2014; 2:813–822 [View Article][PubMed]
     [Google Scholar]
  26. Zhou J, Chu H, Li C, Wong BH, Cheng ZS et al. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis. J Infect Dis 2014; 209:1331–1342 [View Article][PubMed]
     [Google Scholar]
  27. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA. Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study. Int J Infect Dis 2014; 20:42–46 [View Article][PubMed]
     [Google Scholar]
  28. Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA et al. Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV) – possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis 2013; 17:e792e798 [View Article][PubMed]
     [Google Scholar]
  29. Shalhoub S, Farahat F, Al-Jiffri A, Simhairi R, Shamma O et al. IFN-α2a or IFN-β1a in combination with ribavirin to treat Middle East respiratory syndrome coronavirus pneumonia: a retrospective study. J Antimicrob Chemother 2015; 70:2129–2132 [View Article][PubMed]
     [Google Scholar]
  30. Al Ghamdi M, Alghamdi KM, Ghandoora Y, Alzahrani A, Salah F et al. Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia. BMC Infect Dis 2016; 16:174 [View Article][PubMed]
     [Google Scholar]
  31. Who Mers-Cov Research Group State of Knowledge and data gaps of Middle East respiratory syndrome coronavirus (MERS-CoV) in humans. PLoS Curr 2013; 5: [View Article][PubMed]
     [Google Scholar]
  32. Jones BM, Ma ES, Peiris JS, Wong PC, Ho JC et al. Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids. Clin Exp Immunol 2004; 135:467–473 [View Article][PubMed]
     [Google Scholar]
  33. Zhang X, Alekseev K, Jung K, Vlasova A, Hadya N et al. Cytokine responses in porcine respiratory coronavirus-infected pigs treated with corticosteroids as a model for severe acute respiratory syndrome. J Virol 2008; 82:4420–4428 [View Article][PubMed]
     [Google Scholar]
  34. Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol 2004; 31:304–309 [View Article][PubMed]
     [Google Scholar]
  35. Kim SH, Hong SB, Yun SC, Choi WI, Ahn JJ et al. Corticosteroid treatment in critically ill patients with pandemic influenza A/H1N1 2009 infection: analytic strategy using propensity scores. Am J Respir Crit Care Med 2011; 183:1207–1214 [View Article][PubMed]
     [Google Scholar]
  36. Chan JF, Yao Y, Yeung ML, Deng W, Bao L et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015; 212:1904–1913 [View Article][PubMed]
     [Google Scholar]
  37. Khalid M, Al Rabiah F, Khan B, Al Mobeireek A, Butt TS et al. Ribavirin and interferon-α2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases. Antivir Ther 2015; 20:87–91 [View Article][PubMed]
     [Google Scholar]
  38. Kim UJ, Won EJ, Kee SJ, Jung SI, Jang HC et al. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-α for Middle East respiratory syndrome. Antivir Ther 2016; 21:455–459 [View Article][PubMed]
     [Google Scholar]
  39. Spanakis N, Tsiodras S, Haagmans BL, Raj VS, Pontikis K et al. Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J Antimicrob Agents 2014; 44:528–532 [View Article][PubMed]
     [Google Scholar]
  40. Strayer DR, Dickey R, Carter WA. Sensitivity of SARS/MERS CoV to interferons and other drugs based on achievable serum concentrations in humans. Infect Disord Drug Targets 2014; 14:37–43 [View Article][PubMed]
     [Google Scholar]
  41. Al-Tawfiq JA, Memish ZA. Update on therapeutic options for Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Expert Rev Anti Infect Ther 2017; 15:269–275 [View Article][PubMed]
     [Google Scholar]
  42. Public Health England/ISARIC 2015; Treatment of MERS-CoV; information for clinicians. Clinical decision-making support for treatment of MERS-CoV patients. www.google.ie/?gws_rd=ssl#q=public+health+england+treatment+mers-cov [Accessed 21 October 2016]
  43. de Groot RJ, Baker SC, Baric R, Enjuanes L, Gorbalenya AE et al. Family Coronaviridae. In King AMQ, Adams MJ, Carstens EB, Lefkowitz EJ. (editors) Virus Taxonomy: Classification and Nomenclature of Viruses. Ninth Report of the International Committee on Taxonomy of Viruses London, United Kingdom: Academic Press; 2012 pp. 806–820
     [Google Scholar]
  44. Reusken CB, Raj VS, Koopmans MP, Haagmans BL. Cross host transmission in the emergence of MERS coronavirus. Curr Opin Virol 2016; 16:55–62 [View Article][PubMed]
     [Google Scholar]
  45. Corman VM, Ithete NL, Richards LR, Schoeman MC, Preiser W et al. Rooting the phylogenetic tree of middle East respiratory syndrome coronavirus by characterization of a conspecific virus from an African bat. J Virol 2014; 88:11297–11303 [View Article][PubMed]
     [Google Scholar]
  46. Ithete NL, Stoffberg S, Corman VM, Cottontail VM, Richards LR et al. Close relative of human Middle East respiratory syndrome coronavirus in bat, South Africa. Emerg Infect Dis 2013; 19:1697–1699 [View Article][PubMed]
     [Google Scholar]
  47. Rambaut A. 2014; MERS-Coronavirus molecular epidemiology and genetic analysis – Origin and evolution. http://epidemic.bio.ed.ac.uk/coronavirus_analysis [Accessed 14 June 2016]
  48. Mackay IM, Arden KE. MERS coronavirus: diagnostics, epidemiology and transmission. Virol J 2015; 12:222 [View Article][PubMed]
     [Google Scholar]
  49. van Boheemen S, de Graaf M, Lauber C, Bestebroer TM, Raj VS et al. Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. mBio 2012; 3:e00473-12 [View Article][PubMed]
     [Google Scholar]
  50. Scobey T, Yount BL, Sims AC, Donaldson EF, Agnihothram SS et al. Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus. Proc Natl Acad Sci USA 2013; 110:16157–16162 [View Article][PubMed]
     [Google Scholar]
  51. Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog 2013; 9:e1003565 [View Article][PubMed]
     [Google Scholar]
  52. Zhang Z, Shen L, Gu X. Evolutionary dynamics of MERS-CoV: potential recombination, positive selection and transmission. Sci Rep 2016; 6:25049 [View Article][PubMed]
     [Google Scholar]
  53. Du L, Yang Y, Zhou Y, Lu L, Li F et al. MERS-CoV spike protein: a key target for antivirals. Expert Opin Ther Targets 2017; 21:131–143 [View Article][PubMed]
     [Google Scholar]
  54. van Doremalen N, Miazgowicz KL, Milne-Price S, Bushmaker T, Robertson S et al. Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J Virol 2014; 88:9220–9232 [View Article][PubMed]
     [Google Scholar]
  55. Raj VS, Smits SL, Provacia LB, van den Brand JM, Wiersma L et al. Adenosine deaminase acts as a natural antagonist for dipeptidyl peptidase 4-mediated entry of the Middle East respiratory syndrome coronavirus. J Virol 2014; 88:1834–1838 [View Article][PubMed]
     [Google Scholar]
  56. Peck KM, Cockrell AS, Yount BL, Scobey T, Baric RS et al. Glycosylation of mouse DPP4 plays a role in inhibiting Middle East respiratory syndrome coronavirus infection. J Virol 2015; 89:4696–4699 [View Article][PubMed]
     [Google Scholar]
  57. Durai P, Batool M, Shah M, Choi S. Middle East respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control. Exp Mol Med 2015; 47:e181 [View Article][PubMed]
     [Google Scholar]
  58. Graham RL, Baric RS. Recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission. J Virol 2010; 84:3134–3146 [View Article][PubMed]
     [Google Scholar]
  59. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res 2015; 116:76–84 [View Article][PubMed]
     [Google Scholar]
  60. Ho BL, Cheng SC, Shi L, Wang TY, Ho KI et al. Critical assessment of the important residues involved in the dimerization and catalysis of MERS Coronavirus Main protease. PLoS One 2015; 10:e0144865 [View Article][PubMed]
     [Google Scholar]
  61. Cheng KW, Cheng SC, Chen WY, Lin MH, Chuang SJ et al. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res 2015; 115:9–16 [View Article][PubMed]
     [Google Scholar]
  62. Yang Y, Zhang L, Geng H, Deng Y, Huang B et al. The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists. Protein Cell 2013; 4:951–961 [View Article][PubMed]
     [Google Scholar]
  63. Yang Y, Ye F, Zhu N, Wang W, Deng Y et al. Middle East respiratory syndrome coronavirus ORF4b protein inhibits type I interferon production through both cytoplasmic and nuclear targets. Sci Rep 2015; 5:17554 [View Article][PubMed]
     [Google Scholar]
  64. Chu H, Zhou J, Wong BH, Li C, Cheng ZS et al. Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response. Virology 2014; 454-455:197–205 [View Article][PubMed]
     [Google Scholar]
  65. Scheuplein VA, Seifried J, Malczyk AH, Miller L, Höcker L et al. High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus. J Virol 2015; 89:3859–3869 [View Article][PubMed]
     [Google Scholar]
  66. Chu H, Zhou J, Wong BH, Li C, Chan JF et al. Middle East respiratory syndrome Coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis 2016; 213:904–914 [View Article][PubMed]
     [Google Scholar]
  67. Hui DS, Lee N. Adjunctive therapies and immunomodulating agents for severe influenza. Influenza Other Respir Viruses 2013; 7:52–59 [View Article][PubMed]
     [Google Scholar]
  68. Hung IFN, To KKW, Lee CK, Lee KL, Yan WW et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 2013; 144:464–473 [View Article][PubMed]
     [Google Scholar]
  69. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015; 211:80–90 [View Article][PubMed]
     [Google Scholar]
  70. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med 2006; 3:e343 [View Article][PubMed]
     [Google Scholar]
  71. Arabi Y, Balkhy H, Hajeer AH, Bouchama A, Hayden FG et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus 2015; 4:709 [View Article][PubMed]
     [Google Scholar]
  72. Modjarrad K. Treatment strategies for Middle East respiratory syndrome coronavirus. J Virus Erad 2016; 2:1–4[PubMed]
     [Google Scholar]
  73. Arabi YM, Arifi AA, Balkhy HH, Najm H, Aldawood AS et al. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med 2014; 160:389–397 [View Article][PubMed]
     [Google Scholar]
  74. Kapoor M, Pringle K, Kumar A, Dearth S, Liu L et al. Clinical and laboratory findings of the first imported case of Middle East respiratory syndrome coronavirus to the United States. Clin Infect Dis 2014; 59:1511–1518 [View Article][PubMed]
     [Google Scholar]
  75. Wang L, Shi W, Joyce MG, Modjarrad K, Zhang Y et al. Evaluation of candidate vaccine approaches for MERS-CoV. Nat Commun 2015; 6:7712 [View Article][PubMed]
     [Google Scholar]
  76. Du L, Zhao G, Yang Y, Qiu H, Wang L et al. A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein. J Virol 2014; 88:7045–7053 [View Article][PubMed]
     [Google Scholar]
  77. Ying T, Du L, Ju TW, Prabakaran P, Lau CC et al. Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J Virol 2014; 88:7796–7805 [View Article][PubMed]
     [Google Scholar]
  78. Agrawal AS, Ying T, Tao X, Garron T, Algaissi A et al. Passive transfer of A Germline-like neutralizing human monoclonal antibody protects transgenic mice against Lethal Middle East respiratory syndrome coronavirus infection. Sci Rep 2016; 6:31629 [View Article][PubMed]
     [Google Scholar]
  79. Houser KV, Gretebeck L, Ying T, Wang Y, Vogel L et al. Prophylaxis with a Middle East respiratory syndrome coronavirus (MERS-CoV)-Specific human monoclonal antibody protects rabbits from MERS-CoV infection. J Infect Dis 2016; 213:1557–1561 [View Article][PubMed]
     [Google Scholar]
  80. Jiang L, Wang N, Zuo T, Shi X, Poon KM et al. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med 2014; 6:234ra59 [View Article][PubMed]
     [Google Scholar]
  81. Yu X, Zhang S, Jiang L, Cui Y, Li D et al. Structural basis for the neutralization of MERS-CoV by a human monoclonal antibody MERS-27. Sci Rep 2015; 5:13133 [View Article][PubMed]
     [Google Scholar]
  82. Li Y, Wan Y, Liu P, Zhao J, Lu G et al. A humanized neutralizing antibody against MERS-CoV targeting the receptor-binding domain of the spike protein. Cell Res 2015; 25:1237–1249 [View Article][PubMed]
     [Google Scholar]
  83. Qiu H, Sun S, Xiao H, Feng J, Guo Y et al. Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection. Antiviral Res 2016; 132:141–148 [View Article][PubMed]
     [Google Scholar]
  84. Corti D, Passini N, Lanzavecchia A, Zambon M. Rapid generation of a human monoclonal antibody to combat Middle East respiratory syndrome. J Infect Public Health 2016; 9:231–235 [View Article][PubMed]
     [Google Scholar]
  85. Johnson RF, Bagci U, Keith L, Tang X, Mollura DJ et al. 3B11-N, a monoclonal antibody against MERS-CoV, reduces lung pathology in rhesus monkeys following intratracheal inoculation of MERS-CoV Jordan-n3/2012. Virology 2016; 490:49–58 [View Article][PubMed]
     [Google Scholar]
  86. Ohnuma K, Haagmans BL, Hatano R, Raj VS, Mou H et al. Inhibition of Middle East respiratory syndrome coronavirus infection by anti-CD26 monoclonal antibody. J Virol 2013; 87:13892–13899 [View Article][PubMed]
     [Google Scholar]
  87. Lu L, Liu Q, Zhu Y, Chan KH, Qin L et al. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat Commun 2014; 5:3067 [View Article][PubMed]
     [Google Scholar]
  88. Liu S, Xiao G, Chen Y, He Y, Niu J et al. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet 2004; 363:938–947 [View Article][PubMed]
     [Google Scholar]
  89. Bosch BJ, Martina BE, van der Zee R, Lepault J, Haijema BJ et al. Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides. Proc Natl Acad Sci USA 2004; 101:8455–8460 [View Article][PubMed]
     [Google Scholar]
  90. Channappanavar R, Lu L, Xia S, Du L, Meyerholz DK et al. Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J Infect Dis 2015; 212:1894–1903 [View Article][PubMed]
     [Google Scholar]
  91. Du L, Kou Z, Ma C, Tao X, Wang L et al. A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines. PLoS One 2013; 8:e81587 [View Article][PubMed]
     [Google Scholar]
  92. Ma C, Li Y, Wang L, Zhao G, Tao X et al. Intranasal vaccination with recombinant receptor-binding domain of MERS-CoV spike protein induces much stronger local mucosal immune responses than subcutaneous immunization: implication for designing novel mucosal MERS vaccines. Vaccine 2014; 32:2100–2108 [View Article][PubMed]
     [Google Scholar]
  93. Zhang N, Tang J, Lu L, Jiang S, Du L et al. Receptor-binding domain-based subunit vaccines against MERS-CoV. Virus Res 2015; 202:151–159 [View Article][PubMed]
     [Google Scholar]
  94. Zhang N, Channappanavar R, Ma C, Wang L, Tang J et al. Identification of an ideal adjuvant for receptor-binding domain-based subunit vaccines against Middle East respiratory syndrome coronavirus. Cell Mol Immunol 2016; 13:180–190 [View Article][PubMed]
     [Google Scholar]
  95. Tai W, Wang Y, Fett CA, Zhao G, Li F et al. Recombinant receptor-binding domains of multiple Middle East respiratory syndrome coronaviruses (MERS-CoVs) induce cross-neutralizing antibodies against divergent human and camel MERS-CoVs and antibody escape mutants. J Virol 2017; 91:e01651-16 [View Article][PubMed]
     [Google Scholar]
  96. Coleman CM, Liu YV, Mu H, Taylor JK, Massare M et al. Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine 2014; 32:3169–3174 [View Article][PubMed]
     [Google Scholar]
  97. Excler JL, Delvecchio CJ, Wiley RE, Williams M, Yoon IK et al. Toward developing a preventive MERS-CoV Vaccine-Report from a workshop organized by the Saudi Arabia Ministry of Health and the International Vaccine Institute, Riyadh, Saudi Arabia, November 14–15, 2015. Emerg Infect Dis 2016; 22:e1e7 [View Article][PubMed]
     [Google Scholar]
  98. Volz A, Kupke A, Song F, Jany S, Fux R et al. Protective efficacy of recombinant modified vaccinia virus Ankara delivering Middle East respiratory syndrome coronavirus spike glycoprotein. J Virol 2015; 89:8651–8656 [View Article][PubMed]
     [Google Scholar]
  99. Guo X, Deng Y, Chen H, Lan J, Wang W et al. Systemic and mucosal immunity in mice elicited by a single immunization with human adenovirus type 5 or 41 vector-based vaccines carrying the spike protein of Middle East respiratory syndrome coronavirus. Immunology 2015; 145:476–484 [View Article][PubMed]
     [Google Scholar]
  100. Malczyk AH, Kupke A, Prüfer S, Scheuplein VA, Hutzler S et al. A highly immunogenic and protective Middle East respiratory syndrome coronavirus vaccine based on a recombinant measles virus vaccine platform. J Virol 2015; 89:11654–11667 [View Article][PubMed]
     [Google Scholar]
  101. Haagmans BL, van den Brand JM, Raj VS, Volz A, Wohlsein P et al. An orthopoxvirus-based vaccine reduces virus excretion after MERS-CoV infection in dromedary camels. Science 2016; 351:77–81 [View Article][PubMed]
     [Google Scholar]
  102. Inovio 2016; GLS-5300 SynCon® immunotherapy targeting Middle East Respiratory Syndrome. www.inovio.com/products/infectious-disease-vaccines/mers/ [Accessed 18 January 2017]
  103. Muthumani K, Falzarano D, Reuschel EL, Tingey C, Flingai S et al. A synthetic consensus anti-spike protein DNA vaccine induces protective immunity against Middle East respiratory syndrome coronavirus in nonhuman primates. Sci Transl Med 2015; 7:301ra132 [View Article][PubMed]
     [Google Scholar]
  104. Modjarrad K. MERS-CoV vaccine candidates in development: the current landscape. Vaccine 2016; 34:2982–2987 [View Article][PubMed]
     [Google Scholar]
  105. Lau SK, Lau CC, Chan KH, Li CP, Chen H, Skp L, Ccy L et al. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. J Gen Virol 2013; 94:2679–2690 [View Article][PubMed]
     [Google Scholar]
  106. Totura AL, Whitmore A, Agnihothram S, Schäfer A, Katze MG et al. Toll-Like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection. MBio 2015; 6:e00638-1515 [View Article][PubMed]
     [Google Scholar]
  107. de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S et al. MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment. J Gen Virol 2013; 94:1749–1760 [View Article][PubMed]
     [Google Scholar]
  108. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ et al. Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 2013; 3:1686 [View Article][PubMed]
     [Google Scholar]
  109. Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013; 19:1313–1317 [View Article][PubMed]
     [Google Scholar]
  110. Zheng Y, Wang QY. [Bioinformatics analysis on molecular mechanism of Ribavirin and interferon-α in treating MERS-CoV]. Zhonghua Liu Xing Bing Xue Za Zhi 2016; 37:291–293[PubMed]
     [Google Scholar]
  111. Chan JF-W, Yao Y, Yeung M-L, Deng W, Bao L et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of MERS-CoV infection in a nonhuman primate model of common marmoset. J Infect Dis 2015; 212:1904–1913 [View Article]
     [Google Scholar]
  112. Khalid M, Khan B, Al Rabiah F, Alismaili R, Saleemi S et al. Middle Eastern Respiratory syndrome Corona virus (MERS CoV): case reports from a tertiary care hospital in Saudi Arabia. Ann Saudi Med 2014; 34:396–400 [View Article][PubMed]
     [Google Scholar]
  113. Omrani AS, Saad MM, Baig K, Bahloul A, Abdul-Matin M et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. Lancet Infect Dis 2014; 14:1090–1095 [View Article][PubMed]
     [Google Scholar]
  114. Qian Z, Dominguez SR, Holmes KV. Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PLoS One 2013; 8:e76469 [View Article][PubMed]
     [Google Scholar]
  115. Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A et al. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol 2013; 87:5502–5511 [View Article][PubMed]
     [Google Scholar]
  116. Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci USA 2014; 111:15214–15219 [View Article][PubMed]
     [Google Scholar]
  117. Forni D, Filippi G, Cagliani R, de Gioia L, Pozzoli U et al. The heptad repeat region is a major selection target in MERS-CoV and related coronaviruses. Sci Rep 2015; 5:14480 [View Article][PubMed]
     [Google Scholar]
  118. Yamamoto M, Matsuyama S, Li X, Takeda M, Kawaguchi Y et al. Identification of nafamostat as a potent inhibitor of Middle East respiratory syndrome coronavirus S protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay. Antimicrob Agents Chemother 2016; 60:6532–6539 [View Article][PubMed]
     [Google Scholar]
  119. Zhou N, Pan T, Zhang J, Li Q, Zhang X et al. Glycopeptide antibiotics potently inhibit cathepsin L in the late endosome/lysosome and block the entry of Ebola virus, Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus (SARS-CoV). J Biol Chem 2016; 291:9218–9232 [View Article][PubMed]
     [Google Scholar]
  120. Lei J, Mesters JR, Drosten C, Anemüller S, Ma Q et al. Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features. Antiviral Res 2014; 109:72–82 [View Article][PubMed]
     [Google Scholar]
  121. Yang X, Chen X, Bian G, Tu J, Xing Y et al. Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease. J Gen Virol 2014; 95:614–626 [View Article][PubMed]
     [Google Scholar]
  122. Lee H, Lei H, Santarsiero BD, Gatuz JL, Cao S et al. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem Biol 2015; 10:1456–1465 [View Article][PubMed]
     [Google Scholar]
  123. Clasman JR, Báez-Santos YM, Mettelman RC, O'Brien A, Baker SC et al. X-ray Structure and Enzymatic Activity Profile of a Core Papain-like Protease of MERS Coronavirus with utility for structure-based drug design. Sci Rep 2017; 7:40292 [View Article][PubMed]
     [Google Scholar]
  124. Wu CY, Jan JT, Ma SH, Kuo CJ, Juan HF et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA 2004; 101:10012–10017 [View Article][PubMed]
     [Google Scholar]
  125. 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][PubMed]
     [Google Scholar]
  126. Hayden FG, Farrar J, Peiris JS. Towards improving clinical management of Middle East respiratory syndrome coronavirus infection. Lancet Infect Dis 2014; 14:544–546 [View Article][PubMed]
     [Google Scholar]
  127. Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58:4885–4893 [View Article][PubMed]
     [Google Scholar]
  128. Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012; 4:1011–1033 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000565
Loading
A review of candidate therapies for Middle East respiratory syndrome from a molecular perspective
J. Med. Microbiol. 66, 1261 (2017); https://doi.org/10.1099/jmm.0.000565
/content/journal/jmm/10.1099/jmm.0.000565
/content/journal/jmm/10.1099/jmm.0.000565
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error