Medicines Tested Against the Novel Coronavirus That Showed Activity Against Earlier Coronaviruses (MERS-CoV and SARS-CoV)

Coronavirus is the general name of a class of viruses. Apart from the current pandemic, coronaviruses have caused two serious respiratory infectious diseases in the last twenty years:

• Severe Acute Respiratory Syndrome (SARS)
• Middle East Respiratory Syndrome (MERS)

SARS, which emerged in late 2002, caused a large-scale outbreak due to a new coronavirus called SARS-CoV. By August 15, 2003, a total of 8,422 confirmed SARS infections had been reported worldwide, and 916 people had died from the disease. The mortality rate was approximately 10.9%.

Another highly pathogenic disease, MERS, was caused by MERS-CoV, first identified in the Middle East in 2012. MERS-CoV caused severe lower respiratory tract infection, with mortality rates as high as 35%. Despite major efforts to prevent worldwide spread, cases were reported in more than 27 countries. In light of this, coronavirus pneumonia can be considered a serious disease with high infection and mortality rates.

Finally, the first case of the novel coronavirus was identified in Wuhan, China, in late December 2019. The World Health Organization (WHO) named the disease caused by the novel coronavirus (SARS-CoV-2) Covid-19.

SARS-CoV-2 is a β-coronavirus whose genetic characteristics differ substantially from MERS-CoV or SARSr-CoV, with nucleotide homology of approximately 50% and up to 78%, respectively. The resulting COVID-19 is highly contagious and has spread worldwide, causing a pandemic.

- You may be interested: The story of June Almeida, the scientist who discovered the first human coronavirus

No medicine “specific” to SARS-CoV-2 and therefore COVID-19 has currently been developed; medicines in use were developed against earlier viruses and adapted to this disease. Considering that drug development takes 5-10 years, this is of course expected and even how it should be. Finding a suitable therapeutic medicine for COVID-19 remains urgent.

Given the similarity of SARS-CoV-2 to fellow family members SARS-CoV and MERS-CoV, many studies have investigated against SARS-CoV-2 antiviral agents previously observed to be effective against these two viruses.

What Medicines Are Approved / Recommended for COVID-19 Treatment?

As of October 2021, the 5 medicines with the strongest supporting evidence for COVID-19 treatment are:

• A cortisone medicine, dexamethasone (best-known brand names Dekort and Kordexa): a widely accepted medicine for moderate and severe COVID-19. It is available in Turkey, and no special authorization is needed for its use in COVID-19 treatment.
• An antiviral agent, remdesivir (Veklury): FDA-approved for hospitalized patients who are not intubated. It is not licensed in Turkey.
• An IL-6 receptor antagonist, tocilizumab (Actemra): a medicine granted FDA Emergency Use Authorization (Emergency Use Authorization= EUA) for hospitalized COVID-19 patients older than 2. In Turkey, it is licensed for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis. Use for Covid-19 requires off-label authorization.
• A Janus kinase (JAK) inhibitor, baricitinib (Unamity): a medicine granted FDA Emergency Use Authorization for hospitalized COVID-19 patients requiring O2. It is licensed in Turkey for rheumatoid arthritis and atopic dermatitis. Use for COVID-19 requires off-label authorization.
• The antibody cocktail casirivimab and imdevimab (REGEN-COV): an antibody cocktail granted FDA Emergency Use Authorization both for post-exposure prophylaxis (protection) in high-risk people and for treating people who test positive and are at risk of severe COVID-19. It is unavailable in Turkey.

- Related topic: The first pill for COVID-19 treatment may be ready by the end of the year

Some Antiviral Agents Investigated for SARS-CoV-2

Mycophenolic Acid (MPA) is an active substance used particularly in pediatric kidney transplantation, as well as liver and hematopoietic stem cell transplantation, lupus nephritis, nephrotic syndrome, rheumatic disease and autoimmune disorders. An immunosuppressant that inhibits lymphocyte proliferation, MPA also prevents viral RNA replication. In vitro (laboratory) studies have shown MPA to be a potent inhibitor of MERS-CoV. Another study using primate models showed that all animals treated with MPA had a lower average severity of viral load and/or developed fatal disease compared with untreated animals.

A nucleoside analog, Ribavirin, inhibits viral RNA synthesis and has broad-spectrum antiviral activity. Its clinical effect has been inconsistent when used alone for SARS. In vitro studies found that combination with IFN-β showed better antiviral activity against both SARS and MERS, but the clinical effect remained controversial. Nevertheless, in combination with Ribavirin, neither IFN-a2a nor IFN-β1a was effective in reducing MERS-CoV mortality. IFN-a2b and ribavirin treatment were shown to reduce viral replication and the host cell response and improve clinical outcomes in MERS-CoV-infected Rhesus macaques.

Ribavirin has been suggested by in silico analysis to have broad-spectrum effects on different SARS-CoV-2 viral proteins. Detailed molecular techniques showed that ribavirin reduced TMPRSS2 expression (the enzyme allowing fusion of viral and host cell membranes) at both mRNA and protein levels 48 hours after treatment. Its suppressive effect on ACE2 protein expression was shown to depend on cell type. Proteolytic activity assays also demonstrated an inhibitory effect of ribavirin on the TMPRSS2 enzyme. The researchers concluded that ribavirin is a potential antiviral medicine for treatment against SARS-CoV-2.

Lopinavir (LPV) and ritonavir (RTV) are protease inhibitors that can inhibit MERS-CoV's 3C-like protease and modulate apoptosis in human cells. Adding lopinavir/ritonavir to ribavirin treatment in SARS patients was associated with better clinical outcomes than ribavirin alone. Although lopinavir showed an effective cytotoxic concentration below only 50% against MERS-CoV in vitro, experimental LPV/RTV treatment was proven to improve outcomes of MERS-CoV infection in an animal model. In another study, recombinant INF-β1b plus lopinavir/ritonavir led to lower mortality than placebo in patients hospitalized for MERS.

Another study investigated whether combining LPV/RTV with other pneumonia-related adjuvant medicines had a better therapeutic effect on COVID-19. It showed that combination therapy could produce much better efficacy in COVID-19 patients than adjuvant medication alone. However, human trials conducted so far for COVID-19 treatment have not shown significant effectiveness for this pair, and it has not yet been approved.

Chloroquine is an amine acidotropic form of quinine, synthesized by Bayer in Germany in 1934 and introduced approximately 70 years ago as an effective substitute for natural quinine; it was developed primarily to treat malaria. Quinine is a compound found in the bark of Cinchona trees native to Peru and was previously a preferred malaria medicine. For decades, chloroquine was a leading medicine for malaria treatment and prophylaxis. Its in vitro antiviral effect against SARS-CoV was also weaker than against HCoV-OC43 (Human Coronavirus OC43). In vivo studies found that plasma concentrations achieved in mice were not high enough to protect against SARS-CoV infection. Despite extensive use early in the pandemic worldwide, COVID-19 clinical trials did not find it effective, and it is no longer recommended.

Remdesivir (RDV) is a broad-spectrum antiviral medicine with potent in vitro antiviral activity against a range of RNA viruses, including Ebola virus (EBOV), Marburg, MERS-CoV, SARS-CoV, respiratory syncytial virus (RSV), Nipah virus (NİV) and Hendra virus. Remdesivir, sold as Veklury, was approved by the FDA (US Food and Drug Administration) on October 22, 2020 for COVID-19 patients ill enough to require hospitalization. The mechanism of its anti-MERS-CoV activity is most likely premature termination of viral RNA transcription, as demonstrated in biochemical assays using recombinant EBOV, NiV and RSV polymerases. In mice, both prophylactic and therapeutic RDV improve lung function and reduce lung viral loads and severe lung pathology.