To achieve these results, the researchers initially tested the 12,000 drugs in the ReFRAME database, an unrivaled base of molecules, developed with support from the Bill and Melinda Gates Foundation, initially to address urgent unmet medical needs. . ReFRAME thus contains drugs approved by the FDA and other investigational compounds tested or being tested for their safety in humans.
Two types of human cells infected with SARS-CoV-2 were exposed to the 12,000 compounds and, 24 or 48 hours after the exposure, the researchers measured the level of viral infection in the cells to determine if and how effectively them. drugs prevented the virus from replicating. In some cases, researchers have also tested combinations of drugs.
13 antivirals appear to be effective against severe forms
- At the end of this first step, the scientists identified 90 existing drug candidates demonstrating antiviral activity against the coronavirus,
- then, among these compounds, 4 clinically approved drugs (halofantrine, nelfinavir, simeprevir and manidipine) and 9 compounds undergoing tests, all these candidates appearing to be able to be repositioned to be reused as oral antivirals against COVID-19.
- Of the 90 previously selected candidates, 19 were found to increase the activity of remdesivir, a common antiviral therapy for the treatment of COVID-19,
which suggests new possible therapeutic combinations.
Scientists highlight in particular the effectiveness of riboprine-remdesivir combinations (riboprine being a compound tested as a preventive against nausea and surgical infections), and 10-deaaaminopterin-remdesivir, (10-deaaaminopterin being a derivative of the vitamin folic acid).
This work has many implications:
- First of all, the great interest of this research is both its methodology and its exhaustiveness, secondly, it confirms the interest, in the event of a meteoric epidemic, of strategies for repositioning existing drugs;
- the study also raises awareness of the still current need for antivirals to counter the severe complications of COVID-19, “even though we now have effective vaccines against COVID-19”;
- by opening up a certain number of promising avenues, this work, with this first selection of molecules, lays the foundations for new, optimized and more effective antivirals against variants and resistant strains;
- finally, and as is the case with many complex diseases, some of the most effective strategies appear to combine several antivirals.
Lead author Dr Thomas Rogers, professor of immunology and microbiology at Scripps Research and professor of medicine at the University of California San Diego notes that “The advantage of a therapeutic strategy that uses a combination of drugs is that taking a lower dose of each drug in the combination, in general, reduces the risk of side effects.”
“It is essential that we proceed with the utmost rigor in determining what is safe and effective, because it is the fastest and safest way to identify new therapies that will make a difference for patients. “