Study shows new drug combination more effective against SARS-CoV-2

Researchers at the University of Maryland School of Medicine (UMSOM) and University of Pennsylvania Perelman School of Medicine have identified a powerful combination of antivirals to treat COVID-19. The researchers showed that combining the experimental drug brequinar with either of the two drugs already approved by the U.S. Food and Drug Administration for emergency use, remdesivir or molnupiravir, inhibited growth of the SARS-CoV-2 virus in human lung cells and in mice. Their findings suggest that these drugs are more potent when used in combination than individually.

The study was published on February 7, 2022, in Nature.

"We demonstrated that brequinar and molnupiravir work better together than either drug alone in our mouse model of COVID-19," said Co-Principal Investigator Matthew Frieman, PhD, Associate Professor Microbiology and Immunology, and member of the Center for Pathogen Research at UMSOM. "As the virus continues to spread and mutate, we want drugs that are accessible, easy to administer, and effective against the current and future variants."

Though they have not yet been tested in clinical trials, the combinations of treatments identified in their study have the potential to substantially reduce hospitalizations and deaths, said Co-Principal Investigator Sara Cherry, PhD, a professor of Pathology and Laboratory Medicine at the University of Pennsylvania.

There remains an urgent need for therapeutics to treat COVID-19, which has been amplified by emerging threats of new variants that may evade vaccines. In response to this demand, Dr. Cherry, and her team, along with David Schultz, PhD, Technical Director of the Penn High-Throughput Screening Core, screened 18,000 FDA-approved drugs in search of those with antiviral activity using SARS-CoV-2 infected in human lung cells, as they are a major target for the virus.

The researchers identified 122 drugs that showed antiviral activity against the coronavirus. One drug identified was remdesivir, which has been FDA-approved to treat COVID-19 infection via injection through an IV, and another was molnupiravir, which comes in a pill that was authorized for use in December. These drugs look similar to one of the four RNA-building blocks that comprise the genetic sequence of the virus. Remdesivir gets incorporated into the RNA when the virus replicates and essentially stops it from making copies of itself. Molnupiravir gets incorporated into the replicating virus and causes its genetic sequence to change - essentially mutating the virus so it cannot grow.

Another category of drug candidates they identified prevents the virus from making the RNA building blocks the virus needs to replicate. One of these included the experimental drug brequinar, which is currently being tested in clinical trials as a COVID-19 treatment and as part of a potential combination therapy for cancer.

The team hypothesized that combining brequinar with one of fake RNA building block drugs, such as remdesivir or molnupiravir, could work synergistically to create a more potent effect against the virus.

It was through the Bill and Melinda Gates Foundation that Dr. Cherry's program manager suggested her team connect with Dr. Frieman’s group as his laboratory has developed a mouse model for COVID-19. Together, the researchers tested the drugs in lung cells and in mice finding that these combinations were highly effective against multiple variants of the coronavirus.

Also, the research team found that paxlovid - another antiviral pill recently authorized - could be combined with remdesivir or molnupiravir for an "additive" effect against the virus.

"Identifying combinations of antivirals is important, not only to increase the drugs’ potency against the coronavirus, but combining these drugs also reduces the risk of resistance," said Dr. Cherry.

The team is now in the process of testing the drugs against Omicron. They will continue to explore effective combinations of already available drugs against SARS-CoV-2.

The next step for the drug combinations tested in this study is for the Gates Foundation to move these therapeutics forward in clinical trials.

SARS-CoV-2, the virus that causes COVID-19, has infected 382 million people and led to 5 million deaths worldwide.

"We have already lost 5 million people worldwide to the COVID pandemic, and even though we have vaccines and therapies, we are still losing people. Because of this it is of utmost importance that we continue to explore additional and more effective treatment options and antiviral medications," said Dean E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor at the University of Maryland School of Medicine.

Schultz DC, Johnson RM, Ayyanathan K, Miller J, Whig K, Kamalia B, Dittmar M, Weston S, Hammond HL, Dillen C, Ardanuy J, Taylor L, Lee JS, Li M, Lee E, Shoffler C, Petucci C, Constant S, Ferrer M, Thaiss CA, Frieman MB, Cherry S.
Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2.
Nature. 2022 Feb 7. doi: 10.1038/s41586-022-04482-x

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