A recent review, published in Pharmacological Reports, discusses the current efficacy of drug repurposing against COVID-19.
The search
The race to develop a COVID-19 vaccine and effective treatment options is still ongoing. The emergence of SARS-CoV-2 in late 2019 resulted in unique challenges for healthcare professionals to select appropriate therapeutics with very little time available for new drug discovery. Vaccine development takes time, and even with accelerated approval, it could take between 18-20 months to introduce it. In addition, to date, healthcare professionals have had to treat symptoms of COVID-19 rather than the virus itself as there has been no specific treatment available. Therefore, the search for effective therapeutic agents to combat COVID-19 is urgent.
The cost of the development process for new drugs is extremely expensive, with a typically low success rate. In turn, this creates a lag in the productivity of pharmaceutical research to develop new drugs. With an apparent unending pandemic, and taking into consideration the time and cost required to develop new therapies, drug repurposing appears to be a suitable option. Drug repurposing is the process of identifying new indications for existing drugs. Estimates suggest that 75% of known drugs could be repositioned for various diseases. Check out our recent overview on drug repositioning.
Repurposing approaches
Researchers generally use three types of approaches in drug repositioning: computational, biological experimental and mixed. The increasing repository of knowledge and data available in pharmaceuticals has led to a rise in some computational methods. These methods are able to integrate all of this knowledge and data and help provide insight into new signalling pathway and drug mechanisms, side effects and interactions. All of these factors help speed up drug discovery.
COVID-19 drug candidates
With the ongoing public health emergency and lack of effective agents, the World Health Organization (WHO) have identified some therapies which doctors and researchers deem most promising. Many available drugs that have the potential to be repurposed for COVID-19 have been subject to clinical trials. However, the search for other agents cannot stop while waiting for these results. The demand for new, effective agents is critical. Potential drug candidates for repurposing and their mechanisms of action include:
Viral-related targets (genome)
- Remdesivir: A nucleoside analogue that incorporates into viral genomes during replication. Gilead Sciences originally developed the drug against Ebola, yet the drug failed to show effect. It has, however, shown promise in preclinical and clinical research for COVID-19. The drug has been approved for emergency use in the US, India, Singapore, Japan, the EU, Australia and the UK. Initial data from the ACTT-2 Trial showed that remdesivir in combination with baricitinib (JAK inhibitor) is able to reduce recovery time in hospitalised patients.
- Favipiravir: A nucleoside analogue which acts as a competitive inhibitor of RNA-dependent RNA polymerases. Developed by Toyama Chemical, the drug is approved to treat Influenza in Japan. In early 2020, China approved the drug for use against COVID-19 as researchers found that it drastically attenuated illness. In June 2020, the drug was also approved for use in India. Several clinical trials are underway in the UK, Japan, USA and other countries.
- Ribavirin: A guanosine analogue approved for combination treatment of hepatitis C virus and for monotherapy of respiratory syncytial virus. A recent clinical trial showed that ribavirin plus lopinavir/ritonavir combination significantly increased gastrointestinal adverse effects.
Polypeptide packing
- Lopinavir‑ritonavir combination (Kaletra): Abbott Laboratories developed this drug combination as an antiretroviral drug for HIV patients. The combination helps lopinavir remain active for longer. This combination has previously achieved significant viral clearance. However, in the recent RECOVERY clinical trial, the combination showed no clinical benefit, including no improvement in mortality rate.
- Darunavir: A second-generation non-peptide protease inhibitor effective against HIV-1. Using computational drug design methods, researchers identified darunavir as a promising hit for COVID-19 treatment. Despite showing promise in vitro, other evidence suggests that there is limited activity of darunavir against SARS-CoV-2.
Host-related targets (antiviral immunity)
- Interferons: Pegylated interferon alfa-2b acts to target B cells through IFNAR1, enhancing immune response against viral infection. Administered IFNα-2b has shown positive rates of immunoglobulin M (IgM) antibody against several respiratory viruses, including Influenza B. Studies have shown that rates of SAR-CoV-2 infection decreased with IFNα-2b sprays. Scientists have reported a number of adverse events with this therapy but it is generally well tolerated.
- Lopinavir‑ritonavir and interferon‑β: This treatment has previously improved clinical findings and lowered lung viral load in MERS-affected marmosets. It is also being studied in a clinical trial against MERS in Saudi Arabia (MIRACLE). Elsewhere, a recent clinical trial has reported the safety and efficacy of this combination in COVID-19 patients.
Viral uptake pathways
- Chloroquine and hydroxychloroquine: Healthcare professionals use chloroquine to prevent and treat malaria. They use hydroxychloroquine for the treatment of rheumatic diseases, such as rheumatoid arthritis. Although these drugs have moderate in vitro activity against SARS-CoV-2, there is no current evidence that demonstrates significant clinical efficacy. The hydroxychloroquine arms of the RECOVERY and SOLIDARITY trials have stopped due to lack of evidence of its benefit in severe COVID-19.
- Umifenovir: An indole-derivative licensed for decades in Russia and China against Influenza. Results from clinical trials have shown that it leads to a reduction in mortality rate and an increase in recovery rate. Nevertheless, scientists have disputed its effectiveness in some trials.
- Angiotensin receptor blockers (ARBs): ARBs inhibit the action of ACE (isoform of ACE2) and increase ACE2 expression. Patients with diabetes and cardiovascular diseases regularly take ACE inhibitors and ARBs. It is suggested that increased ACE2/ACE ratio may correct endothelial dysfunction and improve host response. Nonetheless, there is conflicting observational evidence about the potential clinical utility of these in COVID-19 patients.
- Statins: These lipid-lowering drugs have anti-inflammatory and immunomodulatory properties that have shown to prevent acute lung injury in many different clinical conditions. Studies have shown that these drugs increase ACE2 expression. Due to statins’ interactions with protease inhibitor drugs, their use in combination therapy with these drugs has been warned.
Proinflammatory cytokines
- Tocilizumab: An immunosuppressive drug mainly used for the treatment of rheumatoid arthritis. Although this drug does not act on the virus, it reduces the cytokine response of the host. However, a recent trial reported disappointing results about the benefits of this drug in COVID-19 patients with pneumonia. Researchers are still testing this drug in the RECOVERY trial.
Other
- Dexamethasone: A corticosteroid used for multiple conditions, such as rheumatic problems and asthma. Preliminary results from the RECOVERY trial revealed its benefits in participants on ventilators.
Future
With a basic understanding of viral pathogenesis and pharmacodynamics of drugs, as well as the use of computational tools, many drugs are currently in the pipeline to be repurposed. The authors of this paper believe that molecular docking is a central technique to identify potential therapeutic agents against COVID-19. As there is no treatment or vaccine for COVID-19, drug repurposing could be the new avenue for COVID-19 treatment.
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