Antiviral compounds block SARS-CoV-2 from entering cells – Washington University in St. Louis School of Medicine

Scientists at Washington University in St. Louis have developed compounds that interfere with many of the important features of the virus that allow it to invade human cells. The compound, called MM3122, has been studied in cells and mice, according to researchers, as a new way to prevent infection and reduce the severity of COVID-19 when given in the early stages of infection. It is promising.

Interestingly, the compound targets an important human protein called transmembrane serine protease 2 (TMPRSS2) that the coronavirus uses to invade and infect human cells.

The study was published online in the minutes of the National Academy of Sciences on October 11.

“Although a good vaccine is available for SARS-CoV-2, we need an effective antiviral drug to help reduce the severity of this pandemic,” said the senior author. Dr. James W. Janetka, Professor of Biochemistry and Molecular Biophysics. “The compounds we are developing prevent the virus from invading cells. We are investigating treatment windows that can administer molecules to mice and protect them from disease. Our ultimate goal is to evolve the molecule into an inhibitor that can be taken by mouth, which could be an effective part of our arsenal of COVID-19 inhibitors. “

This new drug compound strongly blocks another related protein called TMPRSS2 and tryptase found on the surface of the lungs and other cells. SARS-CoV-2, which causes COVID-19, and many other viruses, including coronavirus and influenza, depend on these proteins to infect cells and spread throughout the lungs. After the virus latches into cells of the airway epithelium, the human protein TMPRSS2 cleaves the virus’s peplomer, activates the peaplomer, mediates the fusion of the virus to the cell membrane, and initiates the process of infection. MM3122 blocks the enzymatic activity of the human protein TMPRSS2. When the enzyme is blocked, it disrupts peplomer activation and suppresses membrane fusion.

“The SARS-CoV-2 virus hijacks our own lung cell mechanisms to activate peaplomers, allowing them to bind and invade lung cells,” said Janetka. “By blocking TMPRSS2, if it can be considered a preventative drug in theory, it prevents the virus from invading other cells in the body or lung cells. Currently, COVID -Test this compound in mice in combination with other treatments that target other important parts of the virus to develop effective broad-spectrum antiviral theories that help with 19 and other viral infections. doing.”

When studying cells growing in a laboratory infected with SARS-CoV-2, MM3122 is far superior to remdesivir, a treatment already approved by the Food and Drug Administration for patients with COVID-19. Protected cells from viral damage. Acute safety studies in mice showed that high doses of the compound given for 7 days did not cause any noticeable problems. Researchers have also shown that the compound is equally effective against the original severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).

“Most inhibitors of viral infection work by blocking the step of replication when the virus enters the cell,” the co-authors said. Dr. Sean Welan, Marvin A. Brennecke, a prominent professor, Department of Molecular Microbiology.. “Dr. Janetka identified and improved the molecule that prevents the virus from invading cells first. Since the target of MM3122 is the host protein, this also leads to the emergence of inhibitors resistant viruses. It can pose a bigger barrier to it. “

Janetka added: “This compound is not unique to COVID-19. It has the potential to potentially block viral entry into other coronaviruses and influenza viruses. All of these viruses are the same human to invade lung cells. It depends on proteins. Therefore, blocking human proteins prevents viruses that try to hijack those compounds from entering the cell. “

Janetka and his colleagues are currently working with researchers at the National Institutes of Health (NIH) to test the effectiveness of MM3122 in the treatment and prevention of COVID-19 in animal models of the disease. In animal studies, the drug is given as an injection, but Janetka said she is working on an improved compound that can be taken orally. He is also interested in developing intranasal pathways that deliver drugs more directly to the nasal passages and lungs.

Cooperation with the University of Washington Technology Management Office (OTM), Janetka co-founded a biotechnology startup called ProteXase Therapeutics. The company is licensed for technology that supports the development of compounds for new drug therapies for coronaviruses such as SARS-CoV-2, the original SARS-CoV, and MERS-CoV. ..