Is there a cure for COVID-19 (coronavirus)? Is vaccination the only answer? A few curious scientists asked themselves those questions and then performed extensive research looking for the answer.
In an article published by the American Society for Microbiology; Microbiology: Antimicrobial Agents and Chemotherapy Screening, the authors researched treatments due to their concerns that the pace of drug development and registration for human use was not helping in winning the war against emerging infectious diseases. They screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. MERS-CoV is the beta coronavirus that causes Middle East Respiratory Syndrome, or MERS.
They identified four top compounds with the potential to treat the coronavirus: Chloroquine, Chlorpromazine, Loperamide, and Lopinavir.
Each one was able to inhibit MERS-CoV replication as well inhibit the replication of SARS coronavirus and human coronavirus. Although their protective activity (alone or in combination) remains to be assessed in animal models, their findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction can create a window of time for a human to mount a protective immune response.
The Common Drug with a Potential New Purpose: Treating Coronavirus
Chloroquine/Hydroxychloroquine acts as a zinc ionophore allowing the transport of zinc into the cell. Once levels of zinc rise inside the cell it has the ability to block the RNA (ribonucleic acid) dependent RNA polymerase enzyme used by the virus to replicate.
In 2004, a study published in Biochemical Biophysical Research Communications reported that chloroquine was an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. The authors concluded that chloroquine, an old antimalarial drug, may be considered for immediate use in the prevention and treatment of SARS-CoV infections.
Chloroquine has been used in South Korea with promising results. Some researchers speculate that it may account for the lower morbidity and mortality rates in South Korea vs. Italy.
Hydrohloroquine is a modification of the drug chloroquine, a cheap, and readily available anti-malarial drug. Hydroxychloroquine (Plaquenil) is considered a disease-modifying anti-rheumatic drug. It can decrease the pain and swelling of arthritis. It is used to treat rheumatoid arthritis, some symptoms of lupus, childhood arthritis, and other autoimmune diseases. It is not clear why hydroxychloroquine is effective at treating autoimmune diseases but it is believed that hydroxychloroquine interferes with the communication of cells in the immune system. When treating Lyme disease it is added to antibiotic protocols to increases alkalinity of the cell and the potency of the macrolide antibiotics.
Recently, in a study published on March 9, 2020 in the Journal of Clinical Infectious Disease it was reported that hydroxychloroquine was found to be more potent than chloroquine in vitro. Based on their results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for four days is recommended for SARS-CoV-2 infection. It reached three times the potency of chloroquine phosphate when given 500 mg twice daily, five days in advance.
Hydroxychloroquine should not be used in anyone with retinopathy, and an eye exam is recommended before use.
Chlorpromazine and Triflupromazine: Broad-spectrum Coronavirus Inhibitors?
Two neurotransmitter inhibitors that have been found to inhibit both MERS-CoV and SARS-CoV are chlorpromazine hydrochloride and triflupromazine hydrochloride. Both of these drugs inhibit the dopamine receptor, and they have similar chemical structures. Both chlorpromazine hydrochloride and triflupromazine hydrochloride strongly inhibit MERS-CoV and SARS-CoV, in fact, chlorpromazine hydrochloride has been used to study virus entry by a process called clathrin-mediated endocytosis. This is a process by which cells absorb metabolites, hormones, proteins–and in some cases viruses–by the inward budding of the plasma membrane (invagination). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process. Several viruses including West Nile virus (WNV) and influenza virus use this method. SARS-CoV also utilizes the clathrin-mediated endocytosis pathway for entry into cells, suggesting that this drug may act similarly on MERS-CoV and SARS-CoV and have potential as a broad-spectrum coronavirus inhibitor.
Exploring Aerosol Administration of Lopermide
Loperimide (LPM) is an anti-diarrheal medication that enhances opioid receptors reducing motility in the gastro-intestinal tract. The replication of MERS-CoV in vitro was inhibited by LPM. LPM also inhibits the replication of two other coronaviruses at low concentrations. The problem is that less than 1% of orally taken LPM is absorbed from the gut lumen. Since it is not well absorbed it has limited systemic use, however the authors recommend exploring aerosol administration.
Lopinavir: Protease Inhibitor
The HIV-1 protease inhibitor (PI) Lopinavir (LPV) was shown to inhibit MERS-CoV replication in vitro at a concentration which is in the range of the LPV concentrations in plasma that have been observed in AIDS patients. LPV was previously shown to block the SARS-CoV main protease. However, several anti-HIV protease inhibitors are also known to cause side effects in patients undergoing highly active antiretroviral therapy, including lipodystrophy and insulin resistance. The exact cellular targets of these PIs have not yet been identified, and most likely multiple pathways are involved. It remains to be investigated if the effect of LPV on these intracellular pathways is associated with the anti-CoV activity found here. During the SARS outbreak, treatment with LPV, in combination with ritonavir, was explored with some success in nonrandomized clinical trials.
Other Potential Treatments for Coronavirus
Interferon Gamma and Interleukin 4
Interferon-gamma (IFN) and Interleukin 4 (IL-4) are cytokines capable of downregulates the expression of the SARS corona receptor ACE2 in cells. Interferons (IFNs) inhibit severe acute respiratory syndrome coronavirus (SARS-CoV) replication and might be valuable for SARS treatment. A study published in Virology on September 30, 2006 demonstrated that treatment of cells with interleukin-4 (IL-4) decreased the susceptibility of these cells to SARS-CoV infection. In contrast to IFNs, IL-4 did not show antiviral activity when administered immediately after SARS-CoV infection, suggesting that IL-4 acts early during the SARS-CoV replication cycle. Indeed, binding of recombinant SARS-CoV spike protein to cells was diminished on cells treated with IL-4, but also on cells exposed to IFN-gamma. Consistent with these observations, IL-4 and IFN-gamma down-regulated cell surface expression of angiotensin-converting enzyme 2 (ACE2), the SARS-CoV receptor. Besides diminished ACE2 cell surface expression, ACE2 mRNA levels were also decreased after treatment with these cytokines. These findings suggest that IL-4 and IFN-gamma inhibit SARS-CoV replication partly through down regulation of ACE2.
Ribavirin and Interferon
Broad-spectrum antiviral agents, like the nucleoside analogue ribavirin and interferon (IFN), were tested for their ability to inhibit SARS-CoV infection and were—to a limited extent—used for the treatment of SARS patients during the outbreak. In the case of ribavirin, mixed results were reported from studies in different cell lines, animal models, and patients. Also, the merits of treating SARS patients with immunomodulatory corticosteroids have remained a matter of debate. In animal models, only a very high doses of the compound in combination with IFN-α2b was effective. However, in a small-scale clinical trial, this combination therapy did not benefit critically ill MERS patients. MERS-CoV seems to be considerably more sensitive than SARS-CoV. Treatment with type I IFNs inhibits SARS-CoV and MERS-CoV replication in cell culture and, for protected animals against SARS-CoV or MERS-CoV infection. Based on experiments in cell culture, mycophenolic acid was recently reported to inhibit MERS-CoV infection (41, 42), and others showed that low-micromolar concentrations of cyclosporine inhibit coronavirus replication.
Tamiflu and Similar Antivirals
In hospitals, doctors and nurses are sometimes treating COVID-19 patients with the antiviral drug oseltamivir, or Tamiflu, which seems to suppress the virus’ reproduction in at least some cases. This is somewhat surprising, as Michigan Tech virologist Ebenezer Tumban told Live Science, as Tamiflu was designed to target an enzyme on the influenza virus, not on coronaviruses. The National Institutes of Health has begun a clinical trial at the University of Nebraska Medical Center to test the antiviral remdesivir for COVID-19. In China, doctors are also testing an array of other antivirals originally designed to treat Ebola.
Remdesivir is a nucleotide analog. It blocks the enzyme needed by the virus to replicate. These viruses have a genome that consists of a strand of RNA. To make copies of themselves, they rely on a molecule called a polymerase to string together the individual building blocks of the viral genome. Remdesivir blocks the polymase enzyme by inserting adenosine into the strand of viral DNA causing a cap and not allowing addition nuleotides to be added on. Remdesivir can clear the viral levels in a person, as long as it can interrupt enough replication. The key is that is should be during the early stages of an infection, while the virus is still proliferating.
Is the COVID-19 Solution Already Out There?
Could the answer to this epidemic lie in a simple, readily available anti-malarial drug, or a commonly used antiviral medication, or a protease inhibitor commonly used to treat HIV?
The ongoing MERS-CoV outbreak has made it painfully clear that we need better options for treatment of life-threatening coronavirus infections. Despite the extensive research efforts triggered by the 2003 SARS outbreak no cure has been found. It’s time to fast-track clinical trials of some of these promising drugs.
We also need to be mindful that in patients who develop severe disease, it’s not the virus that’s always the main problem. The body’s own immune system can react by heading into overdrive and causing secondary complications like organ damage. An antiviral can’t head that off once it has begun.
There is much to consider when treating the different types of coronavirus, but diving deeper into existing medication’s effects is most definitely worth more investigation.