Old Dogs Do New Tricks: Repurposing Drugs as SARS-CoV-2 Antivirals
From the original idea to a finished drug can require 12-15 years, one billion USD, and testing of 200,000 to >10,000,000 compounds . Already approved drugs are being studied as antivirals for SARS-CoV-2 to circumvent the drug discovery and development process and provide in immediate need for antivirals for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. A repurposed drug may not provide optimal antiviral activity and symptom treatment, but it may still provide significant benefit to recovering patients. Summarized below are a few of the drugs being considered for SARS-CoV-2 antivirals.
SARS-CoV-2 antiviral drugs act to inhibit different processes in the cell.
• APN01 interferes with interaction of the virus and the receptor on the human cell.
• Chloroquine and hydroxychloroquine interfere with the uptake of the virus into the cell.
• Remdesivir interferes with the replication of the viral RNA genome.
• Lopinavir-ritonavir inhibits the production of viral proteins to inhibit replication of viruses.
APN01: Recombinant angiotensin-converting enzyme 2 (ACE2)
APN01 is recombinant human angiotensin-converting enzyme 2 (rhACE2). ACE2 is a protein produced on the surface of host cells and is required for SARS-CoV-2 viral entry and infection. By administering APN01, the virus will interact more frequently with the rhACE2 than the ACE2 on cell surfaces and thus limit infection . APN01 was originally tested for pulmonary hypertension and acute lung injury/acute respiratory distress syndrome because the drug decreases the risk of lung injury and lung failure . This means that APN01 could help fight SARS-CoV-2 as an antiviral and treatment to decrease risk of lung injury if there is infection. Phase 2 clinical trials for SARS-CoV-2 patients were launched April 2, 2020 and early results will be available soon. APN01 is unique from many of the other drugs under investigation in that the antiviral activity is SARS-CoV-2-specific as opposed to a general antiviral. 
Hydroxychloroquine and chloroquine are structurally very similar, but have differences in strength and toxicity.
Hydroxychloroquine and Chloroquine
Originally malaria antivirals, hydroxychloroquine and chloroquine have been repurposed and are being assessed as SARS-CoV-2 antivirals. Their mechanisms are not fully understood, but it is thought that they interfere with viral entry in two ways. A specific ACE2 glycosylation pattern, or attachment of sugar to a protein, makes the host cell more susceptible to SARS-CoV-2 infection; it is thought that hydroxychloroquine and chloroquine may interfere with this glycosylation pattern to decrease viral susceptibility. Once the virus has bound with the ACE2 receptor, it is transported into the cell via endosomes which are a cellular compartment involved in transport; it is thought that these drugs interfere with endosomal transport of the virus. Hence these drugs are hypothesized to restrict viral infection by decreasing cellular susceptibility to virus and restricting viral uptake. 
The two drugs are structurally very similar, but the minor difference has impactful effects on drug properties. Hydroxychloroquine is 2-3 times less toxic than chloroquine . Chloroquine is more potent than hydroxychloroquine, meaning that a smaller dose of chloroquine can have the same biologic effect. Due to the tradeoff of potency and toxicity, trials are underway for both compounds. A review of the clinical trials to date found study design flaws such as lack of randomization to treatment groups, lack of proper experimental controls, and small sample sizes . These flaws have made results inconclusive and more clinical trial data is needed to assess how well these two drugs work in fighting SARS-CoV-2. Regardless of their efficacy, the World Health Organization put a hold on the clinical trials for hydroxychloroquine due to safety concerns, but chloroquine will be further tested .
Remdesivir was originally intended for treatment of Ebola, but has stolen the spotlight for treatment of SARS-CoV-2. Remdesivir is a prodrug, meaning that it is metabolized into a form that causes the biologic effect of interest. The remdesivir metabolite is an analogue (structurally very similar) to adenosine, which is used by cells to make RNA. SARS-CoV-2’s RNA-dependent RNA polymerase (RdRp) enzyme makes RNA to replicate its genome to spread infection to new cells. When the RdRp enzyme incorporates the remdesivir metabolite, viral replication is halted, thus limiting new virion synthesis. 
In the National Institutes of Allergy and Infectious Disease sponsored clinical trial for remdesivir, SARS-CoV-2 patients’ median duration of disease was significantly decreased from 15 to 11 days. The study suggested a decreased mortality rate with treatment, but more data is needed to determine the statistical significance of the reduction . There has been a massive push to manufacture this drug, in the hopes that it can be utilized more widely to decrease disease duration and potentially reduce mortality rates. As trials continue, remdesivir will be tested in combination with other treatments to see if disease duration and mortality rates can be further decreased. A combinational therapy approach may also address concerns of treatment-resistant virus.
Remdesivir is metabolized in the body into a molecule that is similar to adenosine.
Evaluating approved drugs repurposed as SARS-CoV-2 antivirals has been crucial for fulfilling immediate needs. The results with remdesivir trials have been promising as a first line of treatment; however, it is ultimately of critical importance long-term to continue to develop new SARS-CoV-2-specific antivirals and combinational therapies. This specificity will help improve clinical outcomes and help prevent the emergence of treatment resistant viral strains. In the long run, investing in programs for drugs specific for the coronavirus family may serve to help in future epidemics.
- Hughes et al. “Principles of Early Drug Discovery.” British Journal of Pharmacology (2011)
- Monteil et al. “Inhibition of SARS-CoV-2 Infections in EngineeredHuman Tissues Using Clinical-Grade SolubleHuman ACE2.” Cell (2020)
- Imai, Kuba, Rao et al. “Angiotensin-converting enzyme 2 protects from severe acute lung failure.” Nature (2005)
- “APEIRON Biologics Initiates Phase II Clinical Trial of APN01 for Treatment of COVID-19.” (2020)
- Liu, Cao, Xu et al. “Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.” Cell Discovery (2020)
- McChesney. “Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate.” American Journal of Medicine (1983)
- Chowdhurt et al. “A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID‐19.” Academic Emergency Medicine (2020)
- Cao et al. “A Trial of Lopinavir-Ritonavir in Adults Hospitalized With Severe Covid-19.” New England Journal of Medicine (2020)
- Dorward et al. “Lopinavir/ritonavir: A rapid review of effectiveness in COVID-19.” Center for Evidence-based Medicine (2020)
- Amirian et al. “Compassionate Use of Remdesivir in Covid-19.” One Health (2020)
- NIAID Office of Communications. “NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.” (2020)
- Graff. “WHO pauses trial of hydroxychloroquine in COVID-19 patients due to safety concerns”. (2020)
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