Researchers discover SARS-CoV-2 inhibitors

03/03/2021 Universität Bonn
Pharmacists at the University of Bonn: Substances block key step in
coronavirus replication

A research team of pharmacists at the University of Bonn has discovered two
families of active substances that can block the replication of the
SARS-CoV-2 coronavirus. The drug candidates are able to switch off the the
key enzyme of the virus, the so-called main protease. The study is based on
laboratory experiments. Extensive clinical trials are still required for
their further development as therapeutic drugs. The results have now been
published in the journal "Angewandte Chemie".

In order for the SARS-CoV-2 coronavirus to replicate, it relies on the main
protease as a key enzyme. The virus first has its genome translated from RNA
into a large protein strand. The viral main protease then cuts this protein
chain into smaller pieces, from which the new virus particles are formed.
"The main protease is an extremely promising starting point for coronavirus
drug research," says Prof. Dr. Christa E. Müller of the Pharmaceutical
Institute at the University of Bonn. "If this enzyme is blocked, viral
replication in the body's cells is stopped." The researcher is a member of
the Transdisciplinary Research Area "Life and Health" at the University of

The pharmaceutical chemists designed a large number of potential inhibitors
based on the structure of the main protease and the mechanism by which the
important virus-replicating enzyme works. "A suitable inhibitor must bind
sufficiently tightly to the main protease to be able to block its active
site," says Prof. Dr. Michael Gütschow, who heads an independent research
group on such inhibitors at the Pharmaceutical Institute of the University
of Bonn.

Fluorescent test system

Then the experimental phase began. The researchers developed a new test
system for high-throughput screening. They offered the main protease a
substrate to which a reporter molecule was coupled. When the protease
catalytically cleaved this coupling, the fluorescence of the product was
measurable. However, if a simultaneously administered inhibitor successfully
blocked the activity of the protease, there was no fluorescence. "For most
of the test compounds, we observed no enzyme inhibition. But on rare
occasions in our comprehensive tests, fluorescence was suppressed: These
were the hits we had hoped for in our search for inhibitors of the viral
protease," reports Gütschow.

Like chewing gum at the catalytic center

The researchers' high-throughput screening showed two classes of drugs that
appeared to be particularly promising. Customized compounds of both classes
were then newly synthesized. They stick to the main protease like chewing
gum and block the crucial catalytic center, which prevents the main protease
from preparing the virus replication. "Some of the compounds even have
another effect," Müller reports. "They also inhibit a human enzyme that
helps the virus enter body cells."

The participants contributed very different expertise to the study. "Only
through great collaboration have we been able to design, synthesize and
biochemically characterize suitable drug candidates," says Gütschow. "The
best compounds represent promising lead structures for drug development,"
according to Müller. However, extensive clinical trials have yet to prove
whether these candidates also inhibit SARS coronavirus-2 replication in
humans, Gütschow adds.

Participating institutions and funding

In addition to the lead University of Bonn, the Institute of Virology and
Immunobiology at the University of Würzburg was also involved. The study was
supported with funds from the Pharmaceutical Institute of the University of

Full bibliographic information

Publication: Julian Breidenbach, Carina Lemke, Thanigaimalai Pillaiyar,
Laura Schäkel, Ghazl Al Hamwi, Miriam Diett, Robin Gedschold, Nina Geiger,
Vittoria Lopez, Salahuddin Mirza, Vigneshwaran Namasivayam, Anke C.
Schiedel, Katharina Sylvester, Dominik Thimm, Christin Vielmuth, Lan Phuong
Vu, Maria Zyulina, Jochen Bodem, Michael Gütschow and Christa E. Müller:
Targeting the Main Protease of SARS-CoV-2: From the Establishment of High
Throughput Screening to the Design of Tailored Inhibitors, Angewandte
Chemie, DOI: 10.1002/anie.202016961
Attached files
  • Main protease of the coronavirus with one of thenewly developed inhibitors in the active centre. The individual domains ofthe protein are shown in different colours, the inhibitor in pink. © V.Namasivayam/Pharmazeutisches Institut/Uni Bonn
  • The team (from left): Miriam Diett, LauraSchäkel, Dr. Vigneshwaran Namasivayam, Katharina Sylvester, Ghazl Al Hamwi,Prof. Dr. Christa E. Müller, Julian Breidenbach, Maria Zyulina, Prof. Dr.Michael Gütschow, Lan Phuong Vu and Carina Lemke. © VolkerLannert/University of Bonn

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