Scientists from Washington University School of Medicine in St. Louis have found a chemical substance that disrupts a crucial property of many viruses that permits the viruses to infiltrate human cells.
According to the researchers, the molecule, MM3122, was tested in cells and animals and offers promise as a new strategy to avoid infection or minimise the severity of COVID-19 if administered early in the course of an infection.
In an unusual way, the chemical targets transmembrane serine protease 2 (TMPRSS2), a critical human protein used by coronaviruses to enter and infect human cells.
The new drug compound effectively inhibits TMPRSS2 and another similar protein known as matriptase, both of which are located on the surface of the lung and other cells.
Many viruses rely on these proteins to infect cells and move throughout the lung, including SARS-CoV-2, which causes COVID-19, as well as other coronaviruses and influenza.
After the virus latches onto an airway epithelial cell, the human protein TMPRSS2 cuts the virus’s spike protein, activating the spike protein to mediate fusion of the viral and cellular membranes, so commencing the infection process.
The human protein TMPRSS2’s enzymatic activity is inhibited by MM3122. When the enzyme is inhibited, the activation of the spike protein is disrupted, and membrane fusion is suppressed.
“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,” Janetka said.
“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.”
MM3122 protected cells growing in the lab that were infected with SARS-CoV-2 from viral harm far better than remdesivir, a drug previously authorized by the Food and Drug Administration for patients with COVID-19.
A seven-day acute safety test in mice revealed that huge doses of the chemical did not create any evident difficulties.
The compound was also found to be as effective against the original Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV).
“The majority of inhibitors of viral infection work by blocking steps of replication once the virus is inside the cell,” said co-author Sean Whelan.
“Dr. Janetka has identified and refined a molecule that stops the virus from entering the cell in the first place. As the target of MM3122 is a host protein, this may also pose a larger barrier to the emergence of viruses that are resistant to the inhibitor.”
Janetka further added: “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 working with National Institutes of Health (NIH) researchers to examine the efficacy of MM3122 in treating and preventing COVID-19 in animal models of the disease.
The medicine is given as an injection in animal experiments, but Janetka says they are working on developing a better molecule that can be taken orally. He is also interested in developing an intranasal approach for delivering the medication straight to the nasal passages and lungs.
The findings were published in the Proceedings of the National Academy of Sciences.
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