For decades, antiviral drugs have been used to combat viral infections, including HIV/AIDS and influenza. Now they are a source of hope in the fight against the COVID-19 pandemic. While there is a global effort to develop and test new drugs to fight SARS-CoV-2, the virus that causes COVID-19, that process takes time, during which the disease is rapidly spreading and taking thousands of lives. There is a faster option being pursued simultaneously: testing already-existing drugs to see whether they are effective in treating this new disease. Drug repurposing is being aggressively pursued by the biopharmaceutical industry.
Antiviral drugs aim to interrupt some part of the viral life cycle. Generally, viruses penetrate a host cell, co-opt the host-cell machinery to replicate their genome, assemble new viruses and then escape the cell to spread the infection. Each of these steps requires specific activity from viral proteins and can potentially be blocked by small molecules.
Gilead’s remdesivir, an antiviral drug, is being actively explored for treating COVID-19. It was developed in 2015 as an answer to the Ebola epidemic, though ultimately it was not shown to be effective in treating that disease in clinical trials. It is a nucleotide analog — a chemical that is similar enough to a piece of viral RNA that the virus accidentally incorporates it into its genome when replicating. Remdesivir then blocks the replication process, preventing the virus from copying its genetic material and reproducing. It was previously shown in the lab to be effective in inhibiting the viruses that cause SARS and MERS, which are closely related to SARS-CoV-2, suggesting that it could work against the novel coronavirus as well.
There are multiple clinical trials worldwide testing remdesivir in COVID-19 patients. Gilead has expanded its manufacturing capacity to be able to produce remdesivir in larger quantities should it prove to be effective.
In addition to remdesivir, other antivirals, ones that inhibit RNA polymerase – the protein responsible for replicating the viral genome — are being tested against SARS-CoV-2. These include favipiravir (Avigan), a flu medication produced by Fujifilm subsidiary Toyama Chemical, and ribavirin, a drug used to fight respiratory syncytial virus (RSV). Both are now undergoing clinical trials for COVID-19.
Another contender among existing antiviral medications is lopinavir/ritonavir (Kaletra), an HIV treatment developed by Abbott Laboratories. This is a combination drug used to inhibit a type of protein called a protease that helps process viral proteins into their functional forms. Like HIV, SARS-CoV-2 also relies on a protease, and clinical trials are proceeding to test whether lopinavir/ritonavir has similar activity against the coronavirus.
Unlike the above antivirals, another drug that is being actively investigated to treat COVID-19 is an antimalarial: chloroquine (Resochin) or the related hydroxychloroquine (Plaquenil). Chloroquine has shown potential as an antiviral drug due to its effect on changing the pH of certain compartments of the cell in a way that inhibits viral replication.
Chloroquine has another important function: anti-inflammation, meaning suppression of an overactive immune response. Partly because of this, it is prescribed to treat autoimmune diseases such as lupus and rheumatoid arthritis that are caused by harmful overactivity of the immune system. Severe COVID-19 infections can lead to an over-reaction by the immune system that causes further lung damage to patients, so drugs that can modulate the immune response are another main target for testing treatments.
Other drugs that are already approved to treat rheumatoid arthritis or other autoimmune diseases are now being redeployed against COVID-19. One such family of drugs is JAK inhibitors, which target the immune system protein Janus kinase (JAK). These include tofacitinib (Xeljanz) from Pfizer, ruxolitinib (Jakavi) from Incyte and Novartis, and barticitinib (Olumiant) from Eli Lilly, all of which are being tested as potential treatments for COVID-19.
Another family of anti-inflammatory drugs targets a different protein, interleukin-6 (IL-6), or its receptor IL-6R. After Genentech’s tocilizumab (Actemra), an IL-6R inhibitor, was tested on patients in a Chinese trial and showed promising results, Regeneron and Sanofi began testing their own IL-6R inhibitor, sarilumab (Kevzara), and EUSA Pharma began trials with its IL-6 inhibitor, siltuximab (Sylvant). Unlike the small molecule drugs described above, these three are antibodies: biologic medicines designed to specifically bind to and neutralize a protein target.
In addition to investigating existing drugs, biopharmaceutical companies are conducting massive screens of all the compounds in pharmaceutical libraries to seek out anything that could have efficacy against COVID-19. Many have gathered under the umbrella of an initiative called the COVID-19 Therapeutics Accelerator to share their compound libraries with each other and quickly screen them.
Preliminary data from testing existing drugs have trickled out over the past weeks, but at this early stage the overall findings are, unsurprisingly, inconclusive. Even at the most accelerated possible pace, it will take time before we have the results of compelling clinical trials. In the meantime, the biopharmaceutical industry is leading the charge in finding a therapeutic solution to the COVID-19 pandemic.
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