The latest numbers indicate that COVID-19 cases are on the rise again in the United States. With vaccination rates slowing in many areas, and some areas of the country maintaining large percentages of unvaccinated people, the need for an effective treatment is urgent. Now, a new study finds 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 in human cell cultures and in a mouse model, leading to much lower viral loads.
The work is published in Science in the paper titled, “Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.”
“Inhibitors of the main protease of SARS-CoV-2, like masitinib, could be a new potential way to treat COVID patients, especially in early stages of the disease,” said Savas Tay, PhD, professor of molecular engineering at the University of Chicago. “COVID-19 will likely be with us for many years, and novel coronaviruses will continue to arise. Finding existing drugs that have antiviral properties can be an essential part of treating these diseases.”
The team 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.
When COVID-19 lockdowns began in March 2020, Tay and Nir Drayman, PhD, a postdoctoral fellow in the lab, screened a library of 1,900 clinically safe drugs against OC43, a human beta-coronavirus that causes the common cold and can be studied under regular biosafety conditions. They used cell cultures to determine the drugs’ effect on infection.
Their top 30 drug candidates were tested by Glenn Randall, PhD, professor of microbiology at the University of Chicago, in cell cultures against the SARS-CoV-2 virus. His group found that 20 drugs significantly inhibited replication of both viruses in vitro. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro.
In addition, the orally bioavailable tyrosine kinase inhibitor masitinib was the most potent. In fact, it completely inhibited the 3CL viral enzyme inside the cell, which was confirmed by X-ray crystallography. The drug specifically binds to the 3CL protease active site and inhibits further viral replication.
“That gave us a strong indication of how this drug works, and we became confident that it has a chance to work in humans,” Drayman said.
Though masitinib is currently only approved to treat mast cell tumors in dogs, it has undergone human clinical trials for several diseases, including melanoma, Alzheimer’s disease, multiple sclerosis, and asthma. It has been shown to be safe in humans but does cause side effects, including gastrointestinal disorders and edema, and could potentially raise a patient’s risk for heart disease.
Next, the researchers tested the drug in a mouse model. They found that it reduced the SARS-CoV-2 viral load by more than 99% and reduced inflammatory cytokine levels in mice. In addition, the authors noted that, “mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation.”
In parallel, the researchers also began to test the drug in cell cultures against other viruses and found that it was also effective against picornaviruses, which include Hepatitis A, polio, and rhinoviruses that cause the common cold. In addition, they tested it in cell cultures against three SARS-CoV-2 variants, Alpha, Beta, and Gamma, and found that it worked equally well against them, since it binds to the protease and not to the surface of the virus.
Now, the team is working with the pharmaceutical company that developed the drug (AB Science) to tweak the drug to make it an even more effective antiviral. Meanwhile, masitinib itself could be taken to 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 biggest effect,” Drayman said. “This isn’t the first novel coronavirus outbreak, and it’s not going to be the last. In addition to vaccines, we need to have new treatments available to help those who have been infected.”
