Drug Used To Fight Tumors in Animals May Be Effective in Treating COVID-19

Masitinib, an existing drug used to treat tumors in animals, may be an effective treatment against many types of coronaviruses, including the coronavirus that causes COVID-19.

Scientists using the Advanced Photon Source have found that a drug used to fight tumors in animals may be effective against many types of coronaviruses, including SARS-CoV-2.

Scientists at the University of Chicago have found that the drug masitinib may be effective in treating COVID-19.

The drug, which has undergone several clinical trials for human conditions but has not yet received approval to treat humans, inhibited the replication of SARS-CoV-2, the virus that causes COVID-19, in human cell cultures and in a mouse model, which leads to much lower viral loads.

“(X-ray crystallography) gave us a strong indication of how this drug works, and we gained confidence that it has a chance to work in humans.” — Nir Drayman, University of Chicago

The research team, including scientists at the U.S. Department of Energy’s (DOE) Argonne National Laboratory, also found that the drug could be effective against many types of coronaviruses and picornaviruses. Because of the way it inhibits replication, it has also been shown to remain effective in the face of COVID-19 variants.

“Inhibitors of the key protease of SARS-CoV-2, such as masitinib, may represent a new potential way to treat COVID patients, especially in the early stages of the disease,” said Savas Tay of Pritzker’s School of Molecular Engineering at the University of Chicago, which led the study. “COVID-19 will likely be with us for many years to come, and new coronaviruses will continue to emerge. Finding existing drugs with antiviral properties could be an essential part of treating these diseases.”

The research team used the ultra-bright X-rays from the Advanced Photon Source (APS), a user facility of the U.S. Department of Energy Office of Science in Argonne, to determine the structures of the SARS-CoV-2 virus containing the drug. The results are published in Science.

A race to find COVID-19 treatments

When the COVID-19 lockdowns began in March 2020, Tay and Nir Drayman, a postdoctoral researcher at the University of Chicago who specializes in virology, started thinking about how they could help. To search for a better treatment for the disease, they began screening a library of 1,900 clinically safe drugs against OC43, a coronavirus that causes the common cold and can be studied under regular biosafety conditions. They used cell cultures to determine the effect of the drugs on infection.

They then gave the top 30 drug candidates to Glenn Randall, a professor of microbiology at the University of Chicago, who tested them in cell cultures against the SARS-CoV-2 virus at the Howard Taylor Ricketts Laboratory. Measurements in the lab revealed nearly 20 drugs that inhibit SARS-CoV-2.

They also sent the drug candidates to other collaborators to test against the 3CL protease, the enzyme in coronaviruses that allows them to replicate in a cell. They found that of the drug candidates, masitinib completely inhibited the 3CL viral enzyme in the cell, a fact confirmed by X-ray crystallography by Andrzej Joachimiak and his colleagues at the Structural Biology Center (SBC) at the APS. The drug specifically binds to the active site of the 3CL protease and inhibits further viral replication.

“That gave us a strong indication of how this drug works, and gave us confidence that it has a chance to work in humans,” Drayman said.

While masitinib is currently only approved for the treatment of mast cell tumors in dogs, it has undergone clinical trials in humans for several diseases, including melanoma, Alzheimer’s disease, multiple sclerosis, and asthma. It has been shown to be safe in humans, but causes side effects, including gastrointestinal disturbances and edema, and may potentially increase a patient’s risk of heart disease.

Drug effective against variants, other viruses

Next, the researchers teamed up with colleagues at the University of Louisville to test the drug in a mouse model. They found that it reduced SARS-CoV-2 viral load by more than 99 percent and reduced inflammatory cytokine levels in mice.

At the same time, the researchers also began testing the drug in cell cultures against other viruses and found that it was also effective against picornaviruses, including hepatitis A, polio and rhinoviruses that cause the common cold.

They also tested it in cell cultures against three SARS-CoV-2 variants, Alpha, Beta and Gamma, and found that it worked equally well against them because it binds to the protease and not to the surface of the virus.

Now the team is working with the pharmaceutical company that developed masitinib (AB Science) to tweak the drug to make it an even more effective antiviral. Meanwhile, masitinib itself could be used in human clinical trials in the future to test it as a COVID-19 treatment.

“Masitinib has the potential to be an effective antiviral now, especially when someone is first infected and the antiviral properties of the drug will have the greatest effect,” Drayman said. “This is not the first outbreak of the novel coronavirus and it will not be the last. In addition to vaccines, we need to have new treatments available to help those who are infected.”

Reference: “Masitinib is a broad coronavirus 3CL inhibitor that blocks SARS-CoV-2 replication” by Nir Drayman, Jennifer K. DeMarco, Krysten A. Jones, Saara-Anne Azizi, Heather M. Froggatt, Kemin Tan, Natalia Ivanovna Maltseva , Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S. Kathayat, Mason R. Firpo, Vincent Mastrodomenico, Emily A. Bruce, Madaline M. Schmidt, Robert Jedrzejczak, Miguel Á. Muñoz-Alía, Brooke Schuster, Vishnu Nair, Kyu-yeon Han, Amornrat O’Brien, Anastasia Tomatsidou, Bjoern Meyer, Marco Vignozzi, Dominique Missiakas, Jason W. Botten, Christopher B. Brooke, Hyun Lee, Susan C. Baker, Bryan C. Mounce, Nicholas S. Heaton, William E. Severson, Kenneth E. Palmer, Bryan C. Dickinson, Andrzej Joachimiak, Glenn Randall, and Savas Tay, Aug 20, 2021, Science.
DOI: 10.1126/science.abg5827

The Advanced Photon Source is a user facility of the U.S. Department of Energy (DOE) Office of Science, operated for the DOE Office of Science by Argonne National Laboratory. Additional funding for beamlines used for COVID-19 research at the APS is provided by the National Institutes of Health (NIH) and by the DOE Office of Science Biological and Environmental Research. Additional support for COVID-19 research was provided by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of national DOE labs focused on the response to COVID-19 with funding from the Coronavirus CARES Act.