In efforts to identify a potential therapeutic strategy for COVID-19, Sumit Chanda, Ph.D., director and professor of the Immunity and Pathogenesis Program at Sanford Burnham Prebys Medical Discovery Institute and colleagues have adopted a repositioning drug discovery approach whereby they assess existing drugs that are either being developed for, or are licensed for other indications, to determine if they may work as antivirals for SARS-CoV-2. Their work was carried out using a comprehesive known-drug library called the ReFRAME drug repurposing collection, which was created by Calibr, the drug discovery division of Scripps Research.
We recently spoke with Chanda to learn more about the 21 drug compounds that they recently identified as having activity against SARS-CoV-2.
Laura Lansdowne (LL): Could you tell us more about the 21 existing drug compounds that you found to inhibit SARS-CoV-2 replication? Were there any that look particularly promising?
Sumit Chanda (SC): Of the 21 compounds we identified, we can put them into three categories:
- Compounds that work synergistically with remdesivir, including the chloroquine derivative hanfangchin A (tetrandrine)
- Compounds that halt viral replication in pneumocytes – the lung cells that SARS-CoV-2 primarily infects (apilimod, ONO-5334 and MDL-28170)
- Compounds that are FDA approved (astemizole and clofazimine), as well as remdesivir which recently received Emergency Use Authorization.
It’s most likely that a drug “cocktail” will be needed to effectively treat COVID-19 (similar to how HIV is treated), so it’s good to have drugs that attack the virus differently – especially if we start to see drug resistance emerge. In other words, a cocktail of drugs that can halt viral replication through different mechanisms and in different cell types would be the optimal approach to treat COVID-19.
Of course, I wouldn’t expect all of these to work equally in patients, but they do give us a greater number of “shots on goal” for COVID-19, which we urgently need.
LL: Could you tell us more about the four compounds that were found to work synergistically with remdesivir?
SC: The four compounds we identified as showing some level of synergy with remdesivir are: hanfangchin A, SB-616234-A, MLN-3897 and VBY-825.
- Hanfangchin A is a chloroquine derivative which reached Phase 3 clinical trials, and which has been also shown to inhibit other ebolavirus entry.
- MLN-3897 is a Phase 2 specific antagonist of the C-C Motif Chemokine Receptor 1 (CCR1), developed for the treatment of bone and inflammatory diseases.
- SB-616234-A is a preclinical antagonist of the serotonin receptor 1B.
- VBY-825 is a preclinical cathepsin inhibitor, with high potency against cathepsins B, L, S and V.
LL: What are the key benefits to repurposing drugs, rather than producing novel compounds? How does a “repurposing approach” impact the standard drug development process?
SC: The most significant benefit is time. Since the drugs in repurposing libraries – such as the ReFRAME library that we used – have either already been approved by the US Food and Drug Administration (FDA) or have undergone some safety and toxicology studies, they should generally be safe in humans. Of course, any drug will ultimately have to be studied in the context of the disease in question, but the time to get these medicines to patients can be reduced by many years – in some cases decades – by using a drug repurposing strategy.
LL: When repurposing drugs, how careful do we need to be when considering existing safety data?
SC: That’s a good question. A drug may be safe in an animal model, and even in a healthy human, but may have adverse effects in patients with the disease. It’s possible that a disease creates an environment in the body that will cause a drug to trigger to unwanted effects. This is why drugs have to studied for safety/toxicity in healthy models and in patients with the disease you are trying treat/cure.
LL: Can you tell us about next steps? What further studies/ testing are you planning to carry out?
SC: We are doing more in-depth studies in animal models of COVID-19 and will soon approach the FDA with recommendations based on those results.
Sumit Chanda was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.