Scientists have identified a promising combination of antiviral drugs with great potential for treating COVID-19. The combination of brequinar with remdesivir or molnupiravir inhibited the SARS-CoV-2 virus in human respiratory cells and in mice.
The latter two drugs are approved by the US Food and Drug Administration (FDA) for emergency use.
The discovery, published this week in Nature, is by researchers at the University of Pennsylvania and the University of Maryland School of Medicine. They believe that these drugs are much more potent when used together rather than individually, and such a regimen should be considered in the treatment of people with COVID-19.
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They note that although such a combination has not yet been tested in clinical trials, the results so far indicate that it will be highly effective. The main author of the publication by prof. Sara Cherry emphasizes that “identifying working combinations of antiviral drugs is really important, not only because it will help make drugs more effective against the coronavirus, but also because combining drugs reduces the risk of resistance to them.”
SARS-CoV-2, the virus that causes COVID-19, has so far infected 382 million people worldwide and has led to over 5 million deaths. Despite the growing resistance of societies (due to vaccination and disease), there is still an urgent need to find a cure against this disease, especially as new variants of the virus continue to emerge, which may effectively escape the protection offered by vaccination.
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In response to this demand, Cherry and the team surveyed 18. drugs with antiviral activity. They used human respiratory epithelial cells infected with SARS-CoV-2. They chose them because lung cells are the primary target of the virus.
In total, they identified 122 drugs that simultaneously showed adequate antiviral activity and were selective for the coronavirus. 16 of them belonged to nucleoside analogues – the largest class of antiviral drugs used clinically. Among these 16 there were remivewhich has been approved for the treatment of COVID-19 (injected intravenously) some time ago, and molnupiravir – an oral pill that was approved for use in covid patients in December 2021.
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Another interesting discovery of the research group was an experimental drug called break. It belongs to the group of inhibitors of host nucleoside biosynthesis and works by blocking the production of nucleosides by the body’s own enzymes, which prevents the virus from ‘stealing’ RNA building blocks and replicating. Brequinar is currently in clinical trials as a potential COVID-19 drug and as part of a combination therapy for certain cancers.
Prof. Cherry and her colleagues hypothesized that combining brequinar with a nucleoside analogue such as remdesivir or molnupiravir could act “synergistically” to produce a stronger effect against the virus. Synergistic interactions occur when the combined effect of two or more drugs is greater than the sum of the individual effects of each.
“We thought that the use of a nucleoside analog, while reducing the level of the host building blocks available to the virus, could act as a super drug that would be extremely effective in destroying the virus,” says Prof. Cherry. “And amazing, but it worked: the combination of these measures completely destroyed SARS-CoV-2.”
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The researchers tested their method on human lung cells, but also in mice, and found that the combinations tested are very effective against various strains of coronavirus, including the delta variant. The team is currently testing them against the omicron.
Additives during the research revealed that Paxlovid – an oral antiviral drug that was also recently approved by the FDA – can also be safely combined with remdesivir or molnupiravir for a side effect against SARS-CoV-2.
The next step will be to test the above-mentioned drug combinations in clinical trials.
“As new strains of virus emerge, the need for new treatments will remain critical,” concludes co-author Dr. Matthew Frieman. “However, we now know that there are many potent drug combinations that have the potential to alter the trajectory of the virus.”
Author: Katarzyna Czechowicz
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