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.
This work was funded by grants from the National Institute of Allergy and Infectious Diseases (R01AI074951, R01AI122749, 1R21AI151882, and R01AI140539), the Penn Center for Precision Medicine, Mercatus, and the Bill and Melinda Gates Foundation.
Study author Samuel Constant is CEO of Epithelix.
About the University of Maryland School of Medicine
Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world – with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the U.S., and in the top 15 percent (#27) of all 192 public and private U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu
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Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2
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Study author Samuel Constant is CEO of Epithelix. Mercatus is a funder of the study.