Curtailing COVID – targets for drug repurposing
The coronavirus pandemic has seen the global pharmaceutical industry striving to uncover potential treatments for the SARS-CoV-2 virus. The development of new antiviral medications, however, takes precious time, as these drugs must be subjected to intense scrutiny before they can be deemed safe for human consumption, let alone effective in treating the virus.
In a bid to accelerate the process, therefore, many studies have investigated the effects of repurposing already available antivirals for the treatment of COVID-19 patients. In these urgent and unprecedented times, drug repurposing offers a fast-tracked solution as crucial variables, such as the bioavailability, pharmacology, toxicity profile, and pharmacokinetic data of a given drug, are already well understood.
In this article, we’ll take a deep dive into some of the main contenders, many of which have been candidates for consideration since the virus first made headlines. The graphic below outlines the life cycle of the SARS-CoV-2 virus and points out the stages at which some of the antiviral medications highlighted in this article are purported to have an effect.
Principally used for the treatment of rheumatoid arthritis, barcitinib is a fusion inhibitor sold under the brand names Olumiant, Baricinix, and Baricent, among others.
The drug was first repurposed in March 2020, when it was granted ‘Breakthrough Therapy’ designation for the treatment of alopecia areata, an autoimmune disorder that can cause hair loss on the scalp, face, and other areas of the body. In April 2020, Eli Lilly announced their plans to conduct a clinical trial of baricitinib for the treatment of patients with COVID-19. The results, published in September, suggest that baricitinib in combination with remdesivir reduces time to recovery in hospitalised patients with COVID-19.
Baricitinib’s anti-inflammatory properties may intercept the inflammatory cascade associated with COVID-19. The drug is a Janus kinase (JAK) inhibitor with high potential to bind to and inhibit the enzyme (AAK1) responsible for regulating the process by which SARS-CoV-2 enters host cells (receptor-mediated endocytosis). By disrupting AAK1, it is possible that baricitinib will block viral entry and prevent the virus’ spread.
The drug is not without its downsides, however, one of which is its association with lymphocytopenia, or a reduced white blood cell count. Since patients infected with SARS-CoV-2 are already at risk of a lower lymphocyte count, the use of baricitinib may increase the risk of co-infection.
Camostat mesylate is a serine protease inhibitor licensed in Japan and South Korea to treat pancreatitis. Researchers at the University of Aarhus, Denmark, began investigating the drug’s potential for treating SARS-CoV-2 in April, in combination with hydroxychloroquine.
Camostat mesylate blocks TMPRSS2 receptors, key gateways for SARS-CoV-2 entry into target host cells. By downregulating the expression of SARS-CoV-2 spike (S) protein, the drug may prevent surface fusion, blocking cellular entry of the virus.
Protease inhibitors are a class of antiviral drugs widely used to treat HIV/AIDS and hepatitis C. A number of protease inhibitors have been investigated for COVID-19 repurposing, including lopinavir, darunavir, and atazanavir.
The efficacy of lopinavir has not been determined for COVID-19, but a combination of ritonavir and lopinavir has been used to treat the virus in the USA, Singapore, Japan, and a number of other countries. In June, however, a statement from the Chief Investigators of the Randomised Evaluation of COVID-19 Therapy (RECOVERY) concluded that there were “no clinical benefits from use of lopinavir-ritonavir in hospitalised COVID-19 patients.” Meanwhile, a study revised in May 2020 by an international team found that, “overall, the data do not support use of darunavir for treatment of COVID-19.”
The story is somewhat different for atazanavir, however, which has been found to inhibit SARS-CoV-2 replication and pro-inflammatory cytokine production.
By selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors, protease inhibitors prevent further production of infectious viral particles.
According to researchers, atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication in vero cells, human pulmonary epithelial cell line, and primary monocytes. “Our data strongly suggest that atazanavir and atazanavir/ritonavir should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.”
Drug repurposing offers a chance to accelerate treatment.
Reverse transcription inhibitors
A number of reverse transcription inhibitors have been studied for COVID-19 repurposing. Earlier this month, the USA joined a growing list of countries to have approved remdesivir as a treatment for COVID-19. Though the FDA cautioned that the drug is “not a blockbuster or a miracle drug,” the approval is "supported by data from multiple clinical trials that the agency has rigorously assessed and represents an important scientific milestone in the COVID-19 pandemic," according to Dr Stephen Hahn, commissioner of the FDA.
Meanwhile, faripiravir, sold under the brand name Avigan among others, is used to treat novel influenza in Japan, but recently gained attention for COVID-19 treatment due to its large spectrum antiviral properties. One study in China found faripiravir induced a shorter viral clearance median time for SARS-CoV-2-infected patients, and provide significant improvement in chest CT results compared with a control group.
Another reverse transcription inhibitor, ribavirin, also known as tribavirin, is usually used to treat RSV infection, hepatitis C, and some viral hemorrhagic fevers. It was first patented in 1971 and approved for medical use in 1986, and is featured on the World Health Organization’s List of Essential Medicines. A study Abdo Elfiky of Cairo University, published early on in the pandemic, suggested that ribavirin, alongside sofosbuvir and remdesivir, may be a potent drug in the fight against COVID-19.
Reverse transcription inhibitors prevent viral replication by blocking RNA-dependent RNA polymerase (RdRP), an enzyme which catalyses the replication of RNA. Favipiravir is a guanine nucleotide analogue – by getting integrated with viral DNA, it competes with guanine nucleosides during RNA viral replication, selectively blocking RdRP to prevent further synthesis of viral RNA.
Ribavirin is available in 10mg packs.
Chloroquine and hydroxychloroquine
Chloroquine and hydroxychloruqine are anti-malarial drugs occasionally used to treat rheumatoid arthritis and lupus. Chloroquine is also sometimes used to treat amoebic dysentery outside of the intestine, whilst hydroxychloroquine can be used to treat porphyria cutanea tarda, the most common form of porphyria.
In March 2020, both drugs received widespread media attention after they were referenced by President Donald Trump during a White House address. Dr. Stephen Hahn also made reference to the drug’s potential for repurposing at the address:
“Many Americans have read studies and heard media reports about this drug, chloroquine, which is an anti-malarial drug. It’s already approved, as the President said, for the treatment of malaria, as well as an arthritis condition. That’s a drug that the President has directed us to take a closer look at, as to whether an expanded-use approach to that could be done to actually see if that benefits patients.”
Since that time, evidence has emerged to suggest that chloroquine is unlikely to offer much in the way of value to COVID-19 patients. However, research is ongoing, and it is possible that this conclusion may change.
Several mechanisms have been proposed for chloroquine and hydroxycloroquine mode of action as antiviral molecules.
According to research published by an Italian team in April 2020, the drugs “may inhibit entry, replication and spread of several viruses by different mechanisms, some of which have already been demonstrated or proposed for SARS-CoV-2 infection.” These mechanisms include multiple pathways for the inhibition of viral attachment and entry in the host cell, and for the inhibition of new viral particle maturation and spread.
Chloroquine’s potential to cause detrimental cardiac effects means considerations must be taken before any significant recommendations are made.