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New compound could also be effective against other coronaviruses
Scientists at Washington University School of Medicine in St. Louis have developed a compound that prevents SARS-CoV-2 and related coronaviruses from entering cells. The researchers are working with the National Institutes of Health (NIH) to test the compound in animal models of COVID-19. Pictured is the compound called MM3122 (yellow), which blocks the active site of the human protein TMPRSS2, which the virus hijacks to enter human cells.
“data-medium-file =” https://medicine.wustl.edu/wp-content/uploads/JamesJanetkaAntiviral-300×200.jpg “data-large-file =” https://medicine.wustl.edu/wp-content /uploads/JamesJanetkaAntiviral-700×467.jpg “/>James Janetka
Scientists at Washington University School of Medicine in St. Louis have developed a chemical compound that disrupts a key feature of many viruses that allows viruses to enter human cells. The compound, named MM3122, has been studied in cells and mice and holds great promise for a new way to prevent infection or reduce the severity of COVID-19 if given early in the course of an infection, the researchers said.
In an interesting twist, the compound targets a key human protein called transmembrane serine protease 2 (TMPRSS2), which coronaviruses use to invade and infect human cells.
The study will be published online in the Proceedings of the National Academy of Sciences on October 11.
“There are great vaccines for SARS-CoV-2 now, but we still need effective antiviral drugs to help contain the severity of this pandemic,” said senior author James W. Janetka, PhD, professor of biochemistry and molecular biophysics. “The compound we’re developing prevents the virus from entering the cells. We are investigating the therapeutic window within which the molecule can be administered to mice and protected from disease. Our ultimate goal is to develop the molecules into an oral inhibitor that could become an effective part of our arsenal of COVID-19 inhibitors. “
The new drug effectively blocks TMPRSS2 and another related protein called matriptase, which are found on the surface of the lungs and other cells. Many viruses – including SARS-CoV-2, which causes COVID-19, as well as other coronaviruses and influenza – rely on these proteins to infect cells and spread through the lungs. After the virus attaches to a cell in the airway epithelium, the human TMPRSS2 protein cuts the virus’ spike protein and activates the spike protein to mediate the fusion of the viral and cellular membranes and initiate the infection process. MM3122 blocks the enzymatic activity of the human protein TMPRSS2. When the enzyme is blocked, it interferes with the activation of the spike protein and suppresses membrane fusion.
“The SARS-CoV-2 virus hijacks the machinery of our own lung cells to activate its spike protein, which enables it to attach to and penetrate lung cells,” said Janetka. “By blocking TMPRSS2, the drug prevents the virus from entering other cells in the body or from entering the lung cells at all, if it could theoretically be taken preventively. We are now testing this compound in mice in combination with other treatments targeting other key parts of the virus to develop effective broad spectrum antiviral therapy that would be useful for COVID-19 and other viral infections. “
When studying cells growing in the laboratory that were infected with SARS-CoV-2, MM3122 protected the cells much better from virus damage 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 high doses of the substance administered over seven days did not cause any noticeable problems. The researchers also showed that the compound was just as effective against the original coronavirus with Severe Acute Respiratory Syndrome (SARS-CoV) and the coronavirus with Middle Eastern Respiratory Syndrome (MERS-CoV).
“Most inhibitors of viral infection work by blocking the replication steps once the virus is in the cell,” said co-author Sean Whelan, PhD, Marvin A. Brennecke Distinguished Professor and Head of the Department of Molecular Microbiology. “DR. Janetka has identified and refined a molecule that prevents the virus from entering the cell in the first place. Since the target of MM3122 is a host protein, this can also provide a greater barrier to the emergence of viruses that are resistant to the inhibitor are.”
Janetka added, “This link isn’t just for COVID-19. It could potentially inhibit viral entry for other coronaviruses and even influenza viruses. These viruses all rely on the same human proteins to enter lung cells. So by blocking human proteins, we prevent viruses trying to hijack these proteins from entering cells. “
Janetka and colleagues are now working with researchers from 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 orally. He is also 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 founded a biotechnology startup called ProteXase Therapeutics, which has licensed the technology to link to a new drug therapy for coronaviruses, including SARS-CoV-2 develop Original SARS-CoV and MERS-CoV.
This work was supported by the Siteman Cancer Center, Grant Numbers # 16-FY18-02 and SCC P30CA091842; The Foundation for the Barnes-Jewish Hospital, grant number (BJHF 4984); the National Institutes of Health (NIH), grant numbers R43 CA243941, R43 CA224832, U19 AI142784, P50AI150476, U19 AI070235; the Campaign Dringing Research for Eosinophilic Diseases (CURED) foundation; a Fast Grant from Emergent Ventures at the Mercatus 9 Center; BMBF-RAPID consortium, 01KI1723D and 01KI2006D; RENACO, 01KI20328A; SARS_S1S2 01KI20396; COVIM Consortium, 01KX2021; the state of Lower Saxony, grant number 14-76103-184; and the German Research Foundation, funding numbers PO 716 / 11-1 and PO 716 / 14-1. Working with live SARS-CoV-2 was funded by a Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease Award.
Janetka and co-author Vishnu C. Damalanka are listed as inventors of two Washington University patent applications on these compounds. Janetka and co-author Lidija Klampfer own shares in ProteXase Therapeutics, which licensed the two patent applications.
Mahoney M. et al. A new class of TMPRSS2 inhibitors may block the viral entry of SARS-CoV-2 and MERS-CoV and protect human lung epithelial cells. Procedure of the National Academy of Sciences. October 11, 2021.
The 1,700 faculty physicians at Washington University School of Medicine are also the medical staff for the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and consistently ranks among the best medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with Barnes-Jewish and St. Louis Children’s Hospital.