Scientists at Washington University School of Medicine in St. Louis are collaborating with the NIH researchers to test the MM3122 compound in animal models
The new drug compound potently blocks TMPRSS2 and another related protein called matriptase, which are found on the surface of the lung and other cells.
New antiviral may also be effective against other coronaviruses such as SARS and MERS-CoV and possibly influenza
Scientists at Washington University School of Medicine in St. Louis have developed a chemical compound that interferes with a key feature of many viruses that allows the viruses to invade human cells. The compound, called MM3122, was studied in cells and mice and holds promise as a new way to prevent infection or reduce the severity of COVID-19 if given early in the course of an infection, according to the researchers.
The new drug compound potently blocks TMPRSS2 and another related protein called matriptase, which are found on the surface of the lung and other cells. Many viruses — including SARS-CoV-2, which causes COVID-19, as well as other coronaviruses and influenza — depend on these proteins to infect cells and spread throughout the lung. After the virus latches onto a cell in the airway epithelia, the human protein TMPRSS2 cuts the virus’s spike protein, activating the spike protein to mediate fusion of the viral and cellular membranes, initiating the process of infection. MM3122 is blocking the enzymatic activity of human protein TMPRSS2. When the enzyme is blocked, it perturbs the activation of the spike protein and suppresses membrane fusion.
“The SARS-CoV-2 virus hijacks our own lung cells’ machinery to activate its spike protein, which enables it to bind to and invade lung cells,” said senior author James W. Janetka, PhD, a professor of biochemistry & molecular biophysics. “In blocking TMPRSS2, the drug prevents the virus from entering other cells within the body or from invading the lung cells in the first place if, in theory, it could be taken as a preventive. We’re now testing this compound in mice in combination with other treatments that target other key parts of the virus in efforts to develop an effective broad-spectrum antiviral therapy that would be useful in COVID-19 and other viral infections.”
Studying cells growing in the lab that were infected with SARS-CoV-2, MM3122 protected the cells from viral damage much better than remdesivir, a treatment already approved by the Food and Drug Administration for patients with COVID-19. An acute safety test in mice showed that large doses of the compound given for seven days did not cause any noticeable problems. The researchers also showed that the compound was as effective against the original Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV).
Added Janetka: “This compound is not just for COVID-19. It could potentially inhibit viral entry for other coronaviruses and even influenza virus. These viruses all rely on the same human proteins to invade lung cells. So, by blocking the human proteins, we prevent any virus that tries to hijack those proteins from entering cells.”
Janetka and his colleagues are now collaborating with researchers at the National Institutes of Health (NIH) to test the effectiveness of MM3122 in treating and preventing COVID-19 in animal models of the disease. In animal studies, the drug is given as an injection, but Janetka said they are working to develop an improved compound that could be taken by mouth. He also is interested in developing an intranasal route that would deliver the drug more directly to the nasal passages and lungs.
Working with Washington University’s Office of Technology Management (OTM), Janetka co-founded a biotechnology startup company called ProteXase Therapeutics, which has licensed the technology to help develop the compound into a new drug therapy for coronaviruses, including SARS-CoV-2, the original SARS-CoV and MERS-CoV.
A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells. PNAS, 26 October 2021.