TreatmentUpdate
238

November 2020 

Finding treatments for COVID-19

The SARS-CoV-2 virus is responsible for a global pandemic. Some people infected with this virus will develop complications called COVID-19. As SARS-CoV-2 is new to humanity, it could take several years to develop new antiviral drugs specifically designed to attack this virus.

Given the catastrophic nature of the pandemic, scientists are scrambling to assess drugs approved for one condition (usually another viral infection) to find out if they can be repurposed for SARS-CoV-2 treatment and prevention.

A repurposed drug may not necessarily be the best or most powerful antiviral against SARS-CoV-2. However, until more potent treatments are approved, repurposed drugs are all that will be available.

From the computer to the lab

Some scientists have carried out computer-based simulations that mimic the interaction between antiviral drugs and a key enzyme used by SARS-CoV-2. This enzyme is called RdRp (RNA-dependent RNA polymerase).

Computer simulations of complex interactions at the molecular level are imperfect. But they are a good first step toward identifying compounds that can be tested in coronavirus-infected cells or animals.

Repurposed drugs – caution needed

There have been immense efforts in the past 20 years to repurpose drugs (to find new uses for old drugs) for different diseases. Using computer simulations and/or traditional laboratory testing, even experiments with animals and people, these efforts have not yielded many new uses for old drugs where such new uses have been approved by regulatory authorities, at least in high-income countries.

Potentially, there are many drugs that could be tested in lab studies with cells or animal experiments to assess their effectiveness against SARS-CoV-2. Computer simulations have suggested some possible drugs to test. If the results are promising, such drugs could subsequently be tested in people. Some of these drugs have been mentioned in previous issues of TreatmentUpdate.  

Given the crisis nature of the coronavirus pandemic, scientists and doctors have been forced to take one of the following routes:

  • engage in extensive laboratory experiments with cells and then animals to find candidates worthy of being repurposed against COVID-19; such experiments take time and delay the testing of drugs in people who are sick with COVID-19
  • rush already approved drugs into clinical trials in the hope that they might work against COVID-19

Observers of the massive number of studies that have been launched since the discovery of SARS-CoV-2 have noted that many of these trials were generally not well designed. It should not be surprising that several repurposed drugs have failed to yield major clinical benefit, particularly concerning the endpoint of survival after a diagnosis of COVID-19. An exception so far as been the anti-inflammatory drug dexamethasone.

Professor Aled Edwards, PhD, from the University of Toronto, reviewed the history of drug repurposing with leading scientists, doctors and members of the pharmaceutical industry and gave the following examples of repurposed drugs where a new use for an old drug has been approved by regulatory authorities in high-income countries:

  • thalidomide – originally used as a sedative in pregnant women and withdrawn from sale due its ability to harm the fetus; it was reintroduced and repurposed as a treatment for multiple myeloma
  • sildenafil – initially researchers tested this drug for cardiovascular disease, but it was repositioned for male erectile dysfunction
  • minoxidil – originally used to treat higher-than-normal blood pressure; now most commonly used for treating hair loss

It is possible that other drugs have been discovered through mass screening of almost randomly selected compounds and granted approval by regulatory agencies for the treatment of other diseases. However, it is likely that there is not a huge number of such drugs.

For the future

In the absence of a timely and major breakthrough in COVID-19 treatment, it is likely that the pandemic caused by SARS-CoV-2 will be with us for some time, waxing and waning for reasons not fully understood. Even after the current pandemic has abated, some scientists have predicted that there may be future pandemics caused by other coronaviruses. Therefore, it may be worth launching well-funded programs to discover a range of potential anti-coronavirus drugs and quickly test them in animals and people. In parallel with this, the search for worthy candidates for assessment in repurposing against COVID-19 needs to continue in clinical trials.

Resource

TreatmentUpdate 237 – Antiviral agents for COVID-19

—Sean R. Hosein

REFERENCES:

  1. Edwards A. What are the odds of finding a COVID-19 drug from a lab repurposing screen? Journal of Chemical Information and Modeling. 2020; in press.
  2. Pushpakom S, Iorio F, Eyers PA, et al. Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery. 2019 Jan;18(1):41-58.
  3. Arshad U, Pertinez H, Box H, et al. Prioritization of anti-SARS-Cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics. Clinical Pharmacology and Therapeutics. 2020 Oct;108(4):775-790.
  4. Jockusch S, Tao C, Li X, Anderson TK, et al. A library of nucleotide analogues terminate RNA synthesis catalyzed by polymerases of coronaviruses that cause SARS and COVID-19. Antiviral Research. 2020 Aug;180:104857.
  5. Fintelman-Rodrigues N, Sacramento CQ, Ribeiro Lima C, et al. Atazanavir, alone or in combination with ritonavir, inhibits SARS-CoV-2 replication and proinflammatory cytokine production. Antimicrobial Agents and Chemotherapy. 2020 Sep 21;64(10):e00825-20.
  6. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrobial Agents and Chemotherapy. 2020 Apr 21;64(5):e00399-20.
  7. Park SJ, Yu KM, Kim YI, et al. Antiviral efficacies of FDA-approved drugs against SARS-CoV-2 infection in ferrets. mBio. 2020 May 22;11(3):e01114-20.
  8. Chien M, Anderson TK, Jockusch S, Tao C, Li X, Kumar S, Russo JJ, Kirchdoerfer RN, Ju J. Nucleotide analogues as inhibitors of SARS-CoV-2 polymerase, a key drug target for COVID-19. Journal of Proteome Research. 2020; in press.