COVID-19: New combination of antivirals may be an effective treatment

• Researchers from the University of Pennsylvania identified a combination of antiviral drugs they believe to be effective against the SARS-CoV-2 virus.
• The combination includes the experimental drug brequinar with either the approved drug remdesivir or the approved drug molnupiravir.
• The research group has so far only tested the drug combination in human respiratory cells and mice.
• Scientists plan for further research exploring other drug combinations and testing through clinical trials.

After almost 2 years, the COVID-19 pandemic continues to be an issue around the world. To date, there have been more than 414 million confirmed cases worldwide, and the illness has caused more than 5.8 million deaths.

There are currently a number of different drugs at different stages of research evaluation to test their effectiveness against SARS-CoV-2, the virus that causes COVID-19.

Part of these efforts is a research group from the University of Pennsylvania that has identified a combination of antiviral drugs to treat COVID-19. The blend includes an experimental drug called brequinar with the drugs remdesivir or molnupiravir.

Thus far, researchers have tested this combination on both human respiratory cells and in mice. They believe the results they have seen show the drug combination has the potential to become a promising treatment for COVID-19.

The results from this study appear in the scientific journal Nature.

What are antiviral drugs?

As the name suggests, an antiviral drug combats viruses that get into the human body. Antiviral drugs can enter cells infected with a virus and make it harder for the virus to bind with those cells. Additionally, some antiviral drugs can stop a virus from genetically replicating itself. Antiviral drugs also boost the body’s natural immune system, giving it an edge in fighting off a viral infection.

Because the SARS-CoV-2 virus causes COVID-19, there are currently a number of ongoing research studies around the use of different antiviral drugs to combat the disease.

For example, a new study found a combination of two specific antivirals may help fight off SARS-CoV-2 infection. Pharmaceutical company Pfizer also released data for a new antiviral medication that received approval for use in the United Kingdom in October 2021.

In October 2020, the Food and Drug Administration (FDA) approved the antiviral drug remdesivir as the first treatment for COVID-19 for adults and children over the age of 12. The FDA originally granted an emergency use authorization (EUA) for the drug in May 2020.

Results from three clinical trials found people hospitalized with COVID-19 who received remdesivir had higher rates of symptom improvement compared with receiving a placebo or only standard of care. In January 2022, the FDA expanded the use of remdesivir to certain nonhospitalized people with COVID-19 to treat mild-to-moderate symptoms.

Identifying antiviral drug candidates

Remdesivir is one of the potential drug candidates researchers from the University of Pennsylvania found during their initial screening of about 18,000 drugs.

Researchers examined the drugs for antiviral activity against live SARS-CoV-2 virus inside human epithelial respiratory cells. Using this method, scientists narrowed the field down to 122 drugs that “showed antiviral activity and selectivity” against SARS-CoV-2.

According to principal investigator Dr. Sara Cherry, professor of pathology and laboratory medicine and director of the program for chemogenomic discovery at the University of Pennsylvania, the goal was to identify drugs with antiviral activity against SARS-CoV-2 that are active in respiratory cells. “We identified a number of drugs, including a group of nucleoside analogs, which are the largest group of approved antivirals,” Dr. Cherry told MNT.

“Importantly, we identified the two drugs approved for COVID-19 —remdesivir and molnupiravir, which is under EUA.”

A nucleoside analog is a type of antiviral drug that imitates a human’s natural nucleoside. A nucleoside is an organic molecule in the body comprised of a nitrogenous base and sugar. When used to deliver an antiviral medication, a nucleoside analog enters the body and is able to enter cells where there is a virus. Certain compounds within the nucleoside analog activate, causing it to become a nucleotide. Nucleotides are building blocks of the body’s genetic DNA and RNA code.

“Finding nucleoside analogs, which are mimics of our nucleosides and inhibitors of our enzymes that make nucleosides, led us to the hypothesis that the combination may be more than the sum of their parts, [which] is synergistic,” Dr. Cherry explained. “Synergy is difficult to find, and our discovery may lead to the use of these combinations in treatments.”

Additionally, Dr. Cherry said the researchers found a number of other drugs that fall into diverse classes, including drugs that inhibit a human’s nucleoside biosynthesis enzymes. The nucleoside biosynthesis inhibitor Dr. Cherry refers to is the experimental drug brequinar.

According to the study, a nucleoside biosynthesis inhibitor like brequinar stops the body from producing nucleosides. “This made sense because the [SARS-CoV-2] virus uses the nucleoside building blocks created by our cells to produce the viral RNA,” she added. Ultimately, brequinar helps prevent the SARS-CoV-2 virus from spreading in a person’s body through the use of their RNA.

Testing the drug combination

Once Dr. Cherry and her team identified the antiviral drug combination they felt would be most effective — brequinar plus remdesivir or molnupiravir — they tested the mix on both plated human epithelial lung cells and in mice.

Within both models, scientists observed the drug combination of a nucleoside biosynthesis inhibitor with a nucleoside analog led to a “significant reduction in viral replication” of the SARS-CoV-2 virus.

The research team also found adding an additional antiviral called Paxlovid to the mix could provide an extra boost against the SARS-CoV-2 virus. The FDA approved Paxlovid in December 2021 as the first oral treatment for mild-to-moderate COVID-19 in children and adults over the age of 12 at a high risk of developing severe illness.

For this study, the research team focused on testing these antiviral drug combinations in cells from a human’s lower respiratory tract, such as the lungs.

“We found that the combination is active in a respiratory cell line, as well as in air-liquid interface cultures derived from the nasal epithelium, as well as from bronchial cells,” Dr. Cherry said when asked if she felt this drug therapy would also be effective in the upper respiratory tract. “Therefore, we think that this will be active in the upper respiratory tract in humans.”

Dr. Cherry also believes this antiviral drug combination could potentially be effective against new variants of SARS-CoV-2. “Given that these drugs target RNA replication of the virus, which does not evolve rapidly, and not the Spike protein, it is likely that this combination will be active against emerging variants,” she explained. “Indeed, we found that the combination showed synergy against all of the variants we tested. And we are currently testing Omicron.”

Moving to clinical trials 

As for the next steps for this research, Dr. Cherry said they are currently continuing to explore the use of these drug combinations, as well as other drugs the research team identified in the screening to determine how they impact SARS-CoV-2 and if they could treat COVID-19.

Researchers also mentioned that the next step in testing these drug combinations would include testing in clinical trials.

That is of interest to Dr. Fady Youssef, a board certified pulmonologist, internist, and critical care specialist at MemorialCare Long Beach Medical Center. Dr. Youssef spoke to MNT about this study and said it is encouraging to see possibilities within combinations of these antiviral drugs.

“The biggest question we have is how to identify and treat patients early in their disease state before the virus progresses and causes pneumonia,” he explained. “Many of the interventions we have don’t perform as well when the disease has progressed, including antivirals. The most opportune time to quell a fire is the earliest time you can.”

Another big question, Dr. Youssef continued, “is going to be: How does this perform when applied in [humans]? This is a good precursor that there’s a signal there that’s worth testing. How it’s going to perform in [humans] is unknown and how much activity it’s going to have in the upper respiratory tract versus lower tract is going to depend on how it performs in human trials.”

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