A new combination of antivirals may be an effective treatment

  • Researchers from the University of Pennsylvania identified a combination of antiviral drugs that they believe are 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.
  • So far, the research group has only tested the combination of active ingredients in human airway cells and mice.
  • Scientists are planning further research to explore 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 datethere have been more than 414 million confirmed cases worldwide and the disease has caused more than 5.8 million deaths.

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

Part of that effort is a University of Pennsylvania research group that has identified a combination of antiviral drugs to treat COVID-19. The mixture contains an experimental drug called Brequinar with the drugs remdesivir or molnupiravir.

So far, researchers have tested this combination on both human respiratory cells and 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 of this study appear in the journal nature.

As the name suggests, an antiviral drug fights viruses that enter the human body. Antiviral drugs can enter cells infected with a virus and make it difficult for the virus to attach to those cells. In addition, some antiviral drugs can prevent a virus from replicating itself genetically. Antiviral drugs also boost the body’s natural immune system, giving it an edge in fighting off a viral infection.

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

For example, a new study found a Combination of two specific antivirals can help fight off SARS-CoV-2 infection. Pharmaceutical company Pfizer also released data for a new antiviral drug that received approval for use in the UK 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 12 years of age. The FDA originally granted the drug an emergency use authorization (EUA) in May 2020.

Results from three clinical trials showed that people hospitalized with COVID-19 who received remdesivir had a higher rate of symptom improvement than those who received placebo or just standard of care. In January 2022, the FDA expanded use of remdesivir to certain non-hospitalized people with COVID-19 to treat mild to moderate symptoms.

Remdesivir is one of the potential drug candidates that researchers at the University of Pennsylvania found in their first screening of about 18,000 drugs.

The researchers examined the drugs for their antiviral activity against live SARS-CoV-2 viruses in human airway epithelial cells. Using this method, the scientists narrowed the field to 122 drugs that showed “antiviral activity and selectivity.” SARS-CoV-2.

According to chief investigator dr Sarah Cherry, Professor of Pathology and Laboratory Medicine and Director of the Chemogenomic Discovery Program at the University of Pennsylvania, the goal was to identify drugs with antiviral activity against SARS-CoV-2 that are active in airway cells. “We have identified a number of drugs, including a group of nucleoside analogues, which represent the largest group of approved antivirals,” said Dr. Cherry MNT.

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

ONE nucleoside analogue is a type of antiviral drug that mimics a human’s natural nucleoside. A nucleoside is an organic molecule in the body made up of a nitrogenous base and sugar. When used to deliver an antiviral drug, a nucleoside analogue enters the body and can enter cells where a virus resides. Certain links within the nucleoside analog are activated, making it a nucleotide. Nucleotides are building blocks of the body’s DNA and RNA genetic code.

“The search for nucleoside analogues that are mimics of our nucleosides and inhibitors of our enzymes that make nucleosides led us to hypothesize that the combination might be more than the sum of its parts, [which] is synergistic,” explained Dr. Cherry. “Synergy is hard to find, and our discovery could lead to the use of these combinations in treatments.”

In addition, said Dr. Cherry, the researchers found a number of other drugs that fall into different classes, including drugs that inhibit a person’s nucleoside biosynthetic enzymes. The nucleoside biosynthesis inhibitor referred to by Dr. Cherry is referring to the experimental drug Brequinar.

According to the study, a nucleoside biosynthesis inhibitor such as Brequinar prevents the body from producing nucleosides. “It made sense because the [SARS-CoV-2] Virus uses the nucleoside building blocks made by our cells to produce the virus RNA,” she added. Ultimately, Brequinar helps prevent the spread of the SARS-CoV-2 virus in a person’s body by using their RNA.

after dr Once Cherry and her team had identified the antiviral drug combination that they thought was the most effective — Brequinar plus remdesivir or molnupiravir — they tested the mixture on both plated human lung epithelial cells and mice.

In both models, the scientists observed that the drug combination of a nucleoside biosynthesis inhibitor with a nucleoside analogue resulted in a “significant reduction in viral replication” of the SARS-CoV-2 virus.

The research team also found that adding an extra 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 12 years of age at high risk of developing severe disease.

For this study, the research team focused on testing these antiviral drug combinations in cells from a person’s lower airways, 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 nasal epithelium and bronchial cells,” said Dr. Cherry when asked if she thought this drug therapy would also be effective in the upper respiratory tract. “So we think this will be active in humans in the upper airways.”

dr Cherry also believes this antiviral drug combination could potentially be effective against new variants of SARS-CoV-2. “Given that these drugs target the RNA replication of the virus, which is not rapidly evolving, and not the spike protein, it is likely that this combination will be effective against emerging variants,” she explained. “In fact, we found that the combination showed synergies with all the variants we tested. And we are currently testing Omicron.”

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

The researchers also mentioned that the next step in testing these drug combinations would involve testing in clinical trials.

This is of interest dr Fady Youssef, a board-certified pulmonologist, internist, and critical care specialist at MemorialCare Long Beach Medical Center. dr Youssef spoke to them MNT about this study and said it was encouraging to see opportunities in 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 work as well when the disease is advanced, including antiviral drugs. The best time to put out a fire is as soon as possible.”

Another big question, Dr. Youssef continues, “is: How does this work when applied? [humans]? This is a good harbinger that there is a signal worth testing there. How it will behave in [humans] is unknown and how much activity it will have in the upper airways compared to the lower airways will depend on how it performs in human studies.”

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