The updates on Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemiology, pathogenesis, viral genome and currently available drugs
PDF

Keywords

Virus
Medicinal Chemistry
Replication
Inhibitors

How to Cite

(1)
Jadav, S. S.; Ganta, N. M.; Kumar, A.; Dan, N.; Mohanty, N. P. The Updates on Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Epidemiology, Pathogenesis, Viral Genome and Currently Available Drugs. J Pharm Chem 2016, 3 (2), 10-18. https://doi.org/10.14805/jphchem.2016.art47.

Abstract

The Middle East Respiratory Syndrome (MERS) is caused by the novel coronavirus belongs to the family Betacoronaviridae was first identified in Saudi Arabia during 2012. The first epidemic outbreak of the MERS-CoV has been started reporting in the South Korea and other Asian Countries. The disease was transmitted to humans to humans from the Middle East to other countries through travelling history. The MERS-CoV is responsible for the lower acute and severe respiratory disorder causes the shortness of breath along with fever and cough. The treatment for the disease is purely symptomatic and vaccination is not existed. In the present work we are tried to compile the epidemiology, pathogenesis, viral genome and currently available drugs. At the last the promising approaches for the drug design and development process has been presented.
PDF

References

Mailles, A.; Blanckaert, K.; Chaud, P.; Van der Werf, S.; Lina, B.; Caro, V.; Campese, C.; Guéry, B.; Prouvost, H.; Lemaire, X., First cases of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infections in France, investigations and implications for the prevention of human-to-human transmission, France, May 2013. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Euro Surveill 2013, 12, 19-23

Organization, W. H., Middle East respiratory syndrome coronavirus (MERS-CoV)–update. Saudi Med J 2014, 35 (6), 633-634.

Zaki, A. M.; Van Boheemen, S.; Bestebroer, T. M.; Osterhaus, A. D.; Fouchier, R. A., Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. New Eng J Med 2012, 367 (19), 1814-1820.

https://doi.org/10.1056/NEJMoa1211721

Assiri, A.; McGeer, A.; Perl, T. M.; Price, C. S.; Al Rabeeah, A. A.; Cummings, D. A.; Alabdullatif, Z. N.; Assad, M.; Almulhim, A.; Makhdoom, H., Hospital outbreak of Middle East respiratory syndrome coronavirus. New Eng J Med 2013, 369 (5), 407-416.

https://doi.org/10.1056/NEJMoa1306742

Hui, D. S.; Perlman, S.; Zumla, A., Spread of MERS to South Korea and China. The Lancet Respir Med 2015, 3 (7), 509-510

https://doi.org/10.1016/S2213-2600(15)00238-6

Memish, Z. A.; Almasri, M.; Turkestani, A.; Al-Shangiti, A. M.; Yezli, S., Etiology of severe community-acquired pneumonia during the 2013 Hajj—part of the MERS-CoV surveillance program. Int J Infect Dis 2014, 25, 186-190.

https://doi.org/10.1016/j.ijid.2014.06.003

Control, C. F. D.; Prevention, CDC Health Information for International Travel 2016. Oxford University Press: 2015.

Chan, J. F.; Lau, S. K.; To, K. K.; Cheng, V. C.; Woo, P. C.; Yuen, K.-Y., Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev 2015, 28 (2), 465-522.

https://doi.org/10.1128/CMR.00102-14

Adney, D. R.; van Doremalen, N.; Brown, V. R.; Bushmaker, T.; Scott, D.; de Wit, E.; Bowen, R. A.; Munster, V. J., Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels. Emerg Infect Dis 2014, 20 (12), 1999-2005.

https://doi.org/10.3201/eid2012.141280

Memish, Z. A.; Cotten, M.; Meyer, B.; Watson, S. J.; Alsahafi, A. J.; Al Rabeeah, A. A.; Corman, V. M.; Sieberg, A.; Makhdoom, H. Q.; Assiri, A., Human infection with MERS coronavirus after exposure to infected camels, Saudi Arabia, 2013. Emerg Infect Dis 2014, 20 (6), 1012-1015.

https://doi.org/10.3201/eid2006.140402

Haagmans, B. L.; Al Dhahiry, S. H.; Reusken, C. B.; Raj, V. S.; Galiano, M.; Myers, R.; Godeke, G.-J.; Jonges, M.; Farag, E.; Diab, A., Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation. The Lancet Infect Dis 2014, 14 (2), 140-145.

https://doi.org/10.1016/S1473-3099(13)70690-X

Goh, G. K.-M.; Dunker, A. K.; Uversky, V., Prediction of intrinsic disorder in MERS-CoV/HCoV-EMC supports a high oral-fecal transmission. PLoS Curr 2013, Nov 13, Edition 1.

Cauchemez, S.; Van Kerkhove, M.; Riley, S.; Donnelly, C.; Fraser, C.; Ferguson, N., Transmission scenarios for Middle East Respiratory Syndrome Coronavirus (MERS-CoV) and how to tell them apart. Euro Surveill 2013, 18 (24), 20503.

Gardner, L. M.; MacIntyre, C. R., Unanswered questions about the Middle East respiratory syndrome coronavirus (MERS-CoV). BMC Res Notes 2014, 7 (358), 1-5.

https://doi.org/10.1186/1756-0500-7-358

Banik, G.; Khandaker, G.; Rashid, H., Middle East Respiratory Syndrome Coronavirus "MERS-CoV": Current Knowledge Gaps. Paedtr Respir Rev 2015, 16(3), 197-202.

https://doi.org/10.1016/j.prrv.2015.04.002

Assiri, A.; Al-Tawfiq, J. A.; Al-Rabeeah, A. A.; Al-Rabiah, F. A.; Al-Hajjar, S.; Al-Barrak, A.; Flemban, H.; Al-Nassir, W. N.; Balkhy, H. H.; Al-Hakeem, R. F., Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. The Lancet Infect Dis 2013, 13 (9), 752-761.

https://doi.org/10.1016/S1473-3099(13)70204-4

Guery, B.; Poissy, J.; el Mansouf, L.; Séjourné, C.; Ettahar, N.; Lemaire, X.; Vuotto, F.; Goffard, A.; Behillil, S.; Enouf, V., Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. The Lancet 2013, 381 (9885), 2265-2272.

https://doi.org/10.1016/S0140-6736(13)60982-4

Sharif-Yakan, A.; Kanj, S. S., Emergence of MERS-CoV in the Middle East: origins, transmission, treatment, and perspectives. PLoS Pathog 2014, 10 (12), e1004457.

https://doi.org/10.1371/journal.ppat.1004457

Momattin, H.; Mohammed, K.; Zumla, A.; Memish, Z. A.; Al-Tawfiq, J. A., 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 (10), e792-e798.

https://doi.org/10.1016/j.ijid.2013.07.002

Mackay, I. M.; Arden, K. E., Middle East respiratory syndrome: An emerging coronavirus infection tracked by the crowd. Virus Res 2015, 202, 60-88.

https://doi.org/10.1016/j.virusres.2015.01.021

Breban, R.; Riou, J.; Fontanet, A., Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk. The Lancet 2013, 382 (9893), 694-699.

https://doi.org/10.1016/S0140-6736(13)61492-0

Al-Tawfiq, J. A.; Zumla, A.; Memish, Z. A., Travel implications of emerging coronaviruses: SARS and MERS-CoV. Trav Med Infect Dis 2014, 12 (5), 422-428.

https://doi.org/10.1016/j.tmaid.2014.06.007

Corman, V.; Eckerle, I.; Bleicker, T.; Zaki, A.; Landt, O.; Eschbach-Bludau, M.; Van Boheemen, S.; Gopal, R.; Ballhause, M.; Bestebroer, T., Detection of a novel human coronavirus by real-time reverse-transcription polymerase chain reaction. Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Euro Surveill 2013, 12, 30-35.

Omrani, A. S.; Matin, M. A.; Haddad, Q.; Al-Nakhli, D.; Memish, Z. A.; Albarrak, A. M., A family cluster of Middle East Respiratory Syndrome Coronavirus infections related to a likely unrecognized asymptomatic or mild case. Int J Infect Dis 2013, 17 (9), e668-e672.

https://doi.org/10.1016/j.ijid.2013.07.001

Skowronski, D. M.; Astel, C.; Brunham R. C.; Low, D. E.; Petric, M.; Roper, R. L.; Talbot, P. J.; Babiuk, L. Severe Acute Respiratory Syndrome (SARS): a year in review. Annu Rev Med 2005, 56, 357-381.

https://doi.org/10.1146/annurev.med.56.091103.134135

Shrivastava, A.; Srikantiah, P.; Kumar, A. et al., Outbreaks of Unexplained Neurologic Illness—Muzaffarpur, India, 2013–2014. MMWR Morb Mortal Wkly Rep 2015, 64 (3), 49-76.

Cauchemez, S.; Fraser, C.; Van Kerkhove, M. D.; Donnelly, C. A.; Riley, S.; Rambaut, A.; Enouf, V.; van der Werf, S.; Ferguson, N. M., Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility. The Lancet Infect Dis 2014, 14 (1), 50-56.

https://doi.org/10.1016/S1473-3099(13)70304-9

Petersen, E.; Hui, D. S.; Perlman, S.; Zumla, A., Middle East Respiratory Syndrome–advancing the public health and research agenda on MERS-lessons from the South Korea outbreak. Int J Infect Dis 2015, 36, 54-55.

https://doi.org/10.1016/j.ijid.2015.06.004

Su, S.; Wong, G.; Liu, Y.; Gao, G. F.; Li, S.; Bi, Y., MERS in South Korea and China: a potential outbreak threat? The Lancet 2015, 385 (9985), 2349-2350.

https://doi.org/10.1016/S0140-6736(15)60859-5

Sudre, B., Public health issue. 2015.

De Wit, E.; Rasmussen, A. L.; Falzarano, D.; Bushmaker, T.; Feldmann, F.; Brining, D. L.; Fischer, E. R.; Martellaro, C.; Okumura, A.; Chang, J., Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques. Proc Natl Acad Sci 2013, 110 (41), 16598-16603.

https://doi.org/10.1073/pnas.1310744110

Wang, N.; Shi, X.; Jiang, L.; Zhang, S.; Wang, D.; Tong, P.; Guo, D.; Fu, L.; Cui, Y.; Liu, X., Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res 2013, 23 (8), 986-993.

https://doi.org/10.1038/cr.2013.92

Raj, V. S.; Mou, H.; Smits, S. L.; Dekkers, D. H.; Müller, M. A.; Dijkman, R.; Muth, D.; Demmers, J. A.; Zaki, A.; Fouchier, R. A., Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature 2013, 495 (7440), 251-254.

https://doi.org/10.1038/nature12005

Van Doremalen, N.; Miazgowicz, K. L.; Milne-Price, S.; Bushmaker, T.; Robertson, S.; Scott, D.; Kinne, J.; McLellan, J. S.; Zhu, J.; Munster, V. J., Host species restriction of Middle East respiratory syndrome coronavirus through its receptor, dipeptidyl peptidase 4. J Virol 2014, 88 (16), 9220-9232.

https://doi.org/10.1128/JVI.00676-14

Falzarano, D.; de Wit, E.; Feldmann, F.; Rasmussen, A. L.; Okumura, A.; Peng, X.; Thomas, M. J.; van Doremalen, N.; Haddock, E.; Nagy, L., Infection with MERS-CoV causes lethal pneumonia in the common marmoset. PLos Pathog, 2014, 10 (8), e1004250.

https://doi.org/10.1371/journal.ppat.1004250

Schnittler, H.; Feldmann, H., Molecular pathogenesis of filovirus infections: role of macrophages and endothelial cells. Curr Top Microbiol Immunol 1999, 235, 175-204.

https://doi.org/10.1007/978-3-642-59949-1_10

Hutchinson, K. L.; Villinger, F.; Miranda, M. E.; Ksiazek, T. G.; Peters, C.; Rollin, P. E., Multiplex analysis of cytokines in the blood of cynomolgus macaques naturally infected with Ebola virus (reston serotype). J Med Virol 2001, 65 (3), 561-566.

https://doi.org/10.1002/jmv.2073

Fisher-Hoch, S.; McCormick, J., Pathophysiology and treatment of Lassa fever. In Arenaviruses, Springer 1987, 231-239.

https://doi.org/10.1007/978-3-642-71726-0_10

Kumar, A.; Sharma, N.; Singh, S.; Sasmal, D.; Dev, A., Oral vaccine antigen induced immune response signalling pathways: current and future perspectives. J Vaccines Vaccin 2014, 5, 2-6.

Kumar, A.; Sasmal, D.; Sharma, N., Understanding of complex signaling pathways of immune system: A Review. World J Pharm Pharm Sci 2014, 3 (10), 241-255

Yang, Y.; Zhang, L.; Geng, H.; Deng, Y.; Huang, B.; Guo, Y.; Zhao, Z.; Tan, W., 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 (12), 951-961.

https://doi.org/10.1007/s13238-013-3096-8

Faure, E.; Poissy, J.; Goffard, A.; Fournier, C.; Kipnis, E.; Titecat, M.; Bortolotti, P.; Martinez, L.; Dubucquoi, S.; Dessein, R., Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside. PLoS One 2014, 9 (2), e88716.

https://doi.org/10.1371/journal.pone.0088716

Chu, H.; Zhou, J.; Wong, B. H.-Y.; Li, C.; Cheng, Z.-S.; Lin, X.; Poon, V. K.-M.; Sun, T.; Lau, C. C.-Y.; Chan, J. F.-W., Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response. Virology 2014, 454, 197-205.

https://doi.org/10.1016/j.virol.2014.02.018

Banchereau, J.; Steinman, R. M., Dendritic cells and the control of immunity. Nature 1998, 392 (6673), 245-252.

https://doi.org/10.1038/32588

Josset, L.; Menachery, V. D.; Gralinski, L. E.; Agnihothram, S.; Sova, P.; Carter, V. S.; Yount, B. L.; Graham, R. L.; Baric, R. S.; Katze, M. G., Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. MBio 2013, 4 (3), e00165-13.

https://doi.org/10.1128/mBio.00165-13

Scobey, T.; Yount, B. L.; Sims, A. C.; Donaldson, E. F.; Agnihothram, S. S.; Menachery, V. D.; Graham, R. L.; Swanstrom, J.; Bove, P. F.; Kim, J. D., Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus. Proc Natl Acad Sci 2013, 110 (40), 16157-16162.

https://doi.org/10.1073/pnas.1311542110

Nowotny, N.; Kolodziejek, J., Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels, Oman, 2013. Euro Surveill 2014, 19 (16), 20781.

https://doi.org/10.2807/1560-7917.ES2014.19.16.20781

Lee, H.; Lei, H.; Santarsiero, B. D.; Gatuz, J. L.; Cao, S.; Rice, A. J.; Patel, K.; Szypulinski, M. Z.; Ojeda, I.; Ghosh, A. K., Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV. ACS Chem Biol 2015. 10(6), 1456-1465.

https://doi.org/10.1021/cb500917m

Needle, D.; Lountos, G.; Waugh, D., Structures of the Middle East respiratory syndrome coronavirus 3C-like protease reveal insights into substrate specificity. Acta Crystallogr D 2015, 71 (5), 1102-1111.

https://doi.org/10.1107/S1399004715003521

Bailey-Elkin, B. A.; Knaap, R. C.; Johnson, G. G.; Dalebout, T. J.; Ninaber, D. K.; van Kasteren, P. B.; Bredenbeek, P. J.; Snijder, E. J.; Kikkert, M.; Mark, B. L., Crystal structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) papain-like protease bound to ubiquitin facilitates targeted disruption of deubiquitinating activity to demonstrate its role in innate immune suppression. J Biol Chem 2014, 289 (50), 34667-34682.

https://doi.org/10.1074/jbc.M114.609644

Lei, J.; Mesters, J. R.; Drosten, C.; Anemüller, S.; Ma, Q.; Hilgenfeld, R., Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features. Antiviral Res 2014, 109, 72-82.

https://doi.org/10.1016/j.antiviral.2014.06.011

Dyall, J.; Coleman, C. M.; Venkataraman, T.; Holbrook, M. R.; Kindrachuk, J.; Johnson, R. F.; Olinger, G. G.; Jahrling, P. B.; Laidlaw, M.; Johansen, L. M., Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014, 58 (8), 4885-4893.

https://doi.org/10.1128/AAC.03036-14

Pohjala, L.; Utt, A.; Varjak, M.; Lulla, A.; Merits, A.; Ahola, T.; Tammela, P., Inhibitors of alphavirus entry and replication identified with a stable Chikungunya replicon cell line and virus-based assays. PLoS One 2011, 6 (12), e28923.

https://doi.org/10.1371/journal.pone.0028923

De Wilde, A. H.; Jochmans, D.; Posthuma, C. C.; Zevenhoven-Dobbe, J. C.; van Nieuwkoop, S.; Bestebroer, T. M.; van den Hoogen, B. G.; Neyts, J.; Snijder, E. J., 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 (8), 4875-4884.

https://doi.org/10.1128/AAC.03011-14

Adedeji, A. O.; Singh, K.; Kassim, A.; Coleman, C. M.; Elliott, R.; Weiss, S. R.; Frieman, M. B.; Sarafianos, S. G., Evaluation of SSYA10-001 as a Replication Inhibitor of Severe Acute Respiratory Syndrome, Mouse Hepatitis, and Middle East Respiratory Syndrome Coronaviruses. Antimicrob Agents Chemother 2014, 58 (8), 4894-4898.

https://doi.org/10.1128/AAC.02994-14

Omrani, A. S.; Saad, M. M.; Baig, K.; Bahloul, A.; Abdul-Matin, M.; Alaidaroos, A. Y.; Almakhlafi, G. A.; Albarrak, M. M.; Memish, Z. A.; Albarrak, A. M., Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study. The Lancet Infect Dis 2014, 14 (11), 1090-1095.

https://doi.org/10.1016/S1473-3099(14)70920-X

Dyall, J.; Postnikova, E.; Zhou, H.; Kindrachuk, J.; Johnson, R. F.; Olinger, G. G.; Frieman, M. B.; Holbrook, M. R.; Jahrling, P. B.; Hensley, L., Interferon-β and mycophenolic acid are potent inhibitors of Middle East respiratory syndrome coronavirus in cell-based assays. J Gen Virol 2014, 95 (3), 571-577.

Chan, J. F.; Chan, K.-H.; Kao, R. Y.; To, K. K.; Zheng, B.-J.; Li, C. P.; Li, P. T.; Dai, J.; Mok, F. K.; Chen, H., Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus. J Infect 2013, 67 (6), 606-616.

https://doi.org/10.1016/j.jinf.2013.09.029

Briolant, S.; Garin, D.; Scaramozzino, N.; Jouan, A.; Crance, J., In vitro inhibition of Chikungunya and Semliki Forest viruses replication by antiviral compounds: synergistic effect of interferon-α and ribavirin combination. Antiviral Res 2004, 61 (2), 111-117.

https://doi.org/10.1016/j.antiviral.2003.09.005

Lei, J.; Mesters, J. R.; Drosten, C.; Anemüller, S.; Ma, Q.; Hilgenfeld, R., Crystal structure of the papain-like protease of MERS coronavirus reveals unusual, potentially druggable active-site features. Antiviral Res 2014, 109, 72-82.

https://doi.org/10.1016/j.antiviral.2014.06.011

Ma, C.; Wang, L.; Tao, X.; Zhang, N.; Yang, Y.; Tseng, C.-T. K.; Li, F.; Zhou, Y.; Jiang, S.; Du, L., Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments—the importance of immunofocusing in subunit vaccine design. Vaccine 2014, 32 (46), 6170-6176.

https://doi.org/10.1016/j.vaccine.2014.08.086

Coleman, C. M.; Liu, Y. V.; Mu, H.; Taylor, J. K.; Massare, M.; Flyer, D. C.; Glenn, G. M.; Smith, G. E.; Frieman, M. B., Purified coronavirus spike protein nanoparticles induce coronavirus neutralizing antibodies in mice. Vaccine 2014, 32 (26), 3169-3174.

https://doi.org/10.1016/j.vaccine.2014.04.016

Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.