Antiviral compound blocks SARS-CoV-2 from entering cells
New compound also could be effective against other coronaviruses

Date:
October 12, 2021
Source:
Washington University School of Medicine
Summary:
Scientists 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.



FULL STORY ========================================================================== 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.


==========================================================================
In an interesting twist, the compound targets a key human protein called transmembrane serine protease 2 (TMPRSS2) that coronaviruses harness to
enter and infect human cells.

The study is published online Oct. 11 in the Proceedings of the National Academy of Sciences.

"Great vaccines are now available for SARS-CoV-2, but we still need
effective antiviral medications to help curb the severity of this
pandemic," said senior author James W. Janetka, PhD, a professor of biochemistry & molecular biophysics. "The compound we're developing
prevents the virus from entering cells. We are examining the therapeutic
window within which the molecule can be administered to mice and protect
them from disease. Our ultimate goal is to advance the molecules into an inhibitor that can be taken by mouth and that could become an effective
part of our armamentarium of inhibitors of COVID-19." 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,"
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." 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).



==========================================================================
"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, PhD, the Marvin A. Brennecke Distinguished Professor and head
of the Department of Molecular Microbiology. "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." 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.

This work was funded by Siteman Cancer Center, grant numbers #16-FY18-02
and SCC P30CA091842; The Foundation for 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 Urging 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 country of Lower
Saxony, grant number 14-76103-184; and the German Research Foundation,
grant numbers PO 716/11-1 and PO 716/14-1. Work 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
on two patent applications from Washington University covering these
compounds. Janetka and co-author Lidija Klampfer own stock in ProteXase Therapeutics, which has licensed the two patent filings.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Matthew Mahoney, Vishnu C. Damalanka, Michael A. Tartell, Dong
hee Chung,
Andre' Luiz Lourenc,o, Dustin Pwee, Anne E. Mayer Bridwell, Markus
Hoffmann, Jorine Voss, Partha Karmakar, Nurit P. Azouz, Andrea M.

Klingler, Paul W. Rothlauf, Cassandra E. Thompson, Melody Lee,
Lidija Klampfer, Christina L. Stallings, Marc E. Rothenberg,
Stefan Po"hlmann, Sean P. J. Whelan, Anthony J. O'Donoghue,
Charles S. Craik, James W.

Janetka. A novel class of TMPRSS2 inhibitors potently block
SARS-CoV- 2 and MERS-CoV viral entry and protect human epithelial
lung cells.

Proceedings of the National Academy of Sciences, 2021; 118 (43):
e2108728118 DOI: 10.1073/pnas.2108728118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211012095043.htm

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