Middle East respiratory syndrome coronavirus infection future or investigational therapies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Attending to the fact that MERS-CoV is a relatively novel virus, it represents a great challenge since it hasn't been discovered a therapy yet. Currently, numerous studies are being developed in an attempt of finding a treatment approach for MERS. Some of these include the repurpose of previously approved drugs.[1][2]

Future or Investigational Therapies

The search for broad-spectrum inhibitors aiming to minimize the impact of coronavirus infection remains the major goal. Recent studies are showing the potential use of other drugs and therapies to treat the MERS-CoV, which are based on the experience of treatment of other coronaviruses like the SARS virus. This repurposing of drugs has advantages such as: better availability, lower cost and known safety and tolerability profiles. However, lack of evidence makes these new therapies uncertain.[3]

Cell and animal studies have shown conflicting results: the combination of ribavirin with interferon α-2b in a cell study reduced viral replication[4]; another study in rhesus monkeys with combination of intramuscular ribavirin and interferon α-2b, the group that received the treatment did not develop breathing abnormalities nor radiographic evidence of pneumonia[5]; however, when tried in 5 critically ill patients in Saudi Arabia, this combination was inefficient in all cases, leading to a fatal outcome.[6]

Despite the absence of a specific therapy, some approaches are considered to be more worth of experimentation than others. These include:[7][8][9][10][11]

In Vitro Studies

The development of an antiviral drug is a long-winded process that may not be compatible with the need of a drug to treat coronaviruses, specifically MERS-CoV. Therefore, some studies using existing therapies are being developed in order to find a drug that will likely inhibit the infection by MERS-CoV.[1][12] One of these studies was performed on cell cultures, in the hope of finding a previously approved FDA compounds that would inhibit the replication of the virus in vitro. It was able to find four molecule inhibitors of the replication of MERS-CoV:[1][12]

Although the selectivity index of some compounds was limited, the researchers were able to determine a concentration of drug that inhibited the replication of the virus by more than 80%, preserving the viability of the cell. These drugs were also found to be able to inhibit the replication of other coronaviruses, namely the HCoV-229E and the SARS-CoV. The off-label use of these drugs, particularly when used in combination, might be able to reduce the viral load of the host, therefore halting the course of infection and allowing the building of a proper immune response by the host's immune system.[1]

Further studies will evaluate the potential benefit of the combination of 2+ of these drugs, along with interferon as well. Of the above mentioned, the two presenting as better options for more animal studies and/or off-label use, are the chloroquine and lopinavir. This potential use is due to the fact that these drugs were able to inhibit replication of the virus, in the tested cell cultures, in concentrations that are possible to be achieved in the human plasma.[1]

References

  1. 1.0 1.1 1.2 1.3 1.4 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. (2014). "Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture". Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.03011-14. ISSN 0066-4804.
  2. Dyall, J.; Coleman, C. M.; Hart, B. J.; Venkataraman, T.; Holbrook, M. R.; Kindrachuk, J.; Johnson, R. F.; Olinger, G. G.; Jahrling, P. B.; Laidlaw, M.; Johansen, L. M.; Lear, C. M.; Glass, P. J.; Hensley, L. E.; Frieman, M. B. (2014). "Repurposing of clinically developed drugs for treatment of Middle East Respiratory Coronavirus Infection". Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.03036-14. ISSN 0066-4804.
  3. Dyall J, Coleman CM, Hart BJ, Venkataraman T, Holbrook MR, Kindrachuk J; et al. (2014). "Repurposing of clinically developed drugs for treatment of Middle East Respiratory Coronavirus Infection". Antimicrob Agents Chemother. doi:10.1128/AAC.03036-14. PMID 24841273.
  4. Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H (2013). "Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin". Sci Rep. 3: 1686. doi:10.1038/srep01686. PMC 3629412. PMID 23594967.
  5. Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP; et al. (2013). "Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques". Nat Med. 19 (10): 1313–7. doi:10.1038/nm.3362. PMID 24013700.
  6. Al-Tawfiq JA, Momattin H, Dib J, Memish ZA (2014). "Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study". Int J Infect Dis. 20: 42–6. doi:10.1016/j.ijid.2013.12.003. PMID 24406736.
  7. "Treatment of MERS-CoV: Decision Support Tool".
  8. Guery B, van der Werf S (2013). "Coronavirus: need for a therapeutic approach". Lancet Infect Dis. 13 (9): 726–7. doi:10.1016/S1473-3099(13)70153-1. PMID 23782860.
  9. Ren Z, Yan L, Zhang N, Guo Y, Yang C, Lou Z; et al. (2013). "The newly emerged SARS-like coronavirus HCoV-EMC also has an "Achilles' heel": current effective inhibitor targeting a 3C-like protease". Protein Cell. 4 (4): 248–50. doi:10.1007/s13238-013-2841-3. PMID 23549610.
  10. "WHO-ISARIC joint MERS-CoV Outbreak Readiness Workshop: Clinical management and potential use of convalescent plasma" (PDF).
  11. Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA (2013). "Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)--possible lessons from a systematic review of SARS-CoV therapy". Int J Infect Dis. 17 (10): e792–8. doi:10.1016/j.ijid.2013.07.002. PMID 23993766.
  12. 12.0 12.1 de Wilde AH, Raj VS, Oudshoorn D, Bestebroer TM, van Nieuwkoop S, Limpens RW; et al. (2013). "MERS-coronavirus replication induces severe in vitro cytopathology and is strongly inhibited by cyclosporin A or interferon-α treatment". J Gen Virol. 94 (Pt 8): 1749–60. doi:10.1099/vir.0.052910-0. PMC 3749523. PMID 23620378.