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Targeting the Main ...
Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
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- Altincekic, Nadide (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Jores, Nathalie (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Löhr, Frank (author)
- Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany; Institute of Biophysical Chemistry, Goethe University Frankfurt am Main, Frankfurt, Germany
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- Richter, Christian (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Ehrhardt, Claus (author)
- Department of Biochemistry, University of Zurich, Zurich, Switzerland
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- Blommers, Marcel J.J. (author)
- SavernaTherapeutics, Biel-Benken, Switzerland
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- Berg, Hannes (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Öztürk, Sare (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany
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- Gande, Santosh L. (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Linhard, Verena (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Orts, Julien (author)
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria
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- Abi Saad, Marie Jose (author)
- Department of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria
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- Bütikofer, Matthias (author)
- Swiss Federal Institute of Technology, Laboratory of Physical Chemistry, ETH Zurich, Zürich, Switzerland
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- Kaderli, Janina (author)
- Swiss Federal Institute of Technology, Laboratory of Physical Chemistry, ETH Zurich, Zürich, Switzerland
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- Karlsson, B Göran, 1962 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Svenskt NMR-centrum vid Göteborgs universitet,Department of Chemistry and Molecular Biology,Swedish NMR Centre at Göteborg University,Swedish NMR Centre, Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden; SciLifeLab, University of Gothenburg, Göteborg, Sweden
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- Brath, Ulrika (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Svenskt NMR-centrum vid Göteborgs universitet,Department of Chemistry and Molecular Biology,Swedish NMR Centre at Göteborg University,Swedish NMR Centre, Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
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- Hedenström, Mattias, 1976- (author)
- Umeå universitet,Kemiska institutionen
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- Gröbner, Gerhard (author)
- Umeå universitet,Kemiska institutionen
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- Sauer, Uwe H. (author)
- Umeå universitet,Kemiska institutionen
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- Perrakis, Anastassis (author)
- Oncode Institute and Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, Netherlands
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- Langer, Julian (author)
- Max Planck Institute of Biophysics, Frankfurt am Main, Germany
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- Banci, Lucia (author)
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Via L. Sacconi 6, Sesto Fiorentino, Italy; Consorzio Interuniversitario Risonanze Magnetiche Metalloproteine, Via L. Sacconi 6, Sesto Fiorentino, Italy
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- Cantini, Francesca (author)
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Via L. Sacconi 6, Sesto Fiorentino, Italy; Consorzio Interuniversitario Risonanze Magnetiche Metalloproteine, Via L. Sacconi 6, Sesto Fiorentino, Italy
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- Fragai, Marco (author)
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Via L. Sacconi 6, Sesto Fiorentino, Italy; Consorzio Interuniversitario Risonanze Magnetiche Metalloproteine, Via L. Sacconi 6, Sesto Fiorentino, Italy
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- Grifagni, Deborah (author)
- Magnetic Resonance Center and Department of Chemistry, University of Florence, Via L. Sacconi 6, Sesto Fiorentino, Italy
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- Barthel, Tatjana (author)
- Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, Berlin, Germany
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- Wollenhaupt, Jan (author)
- Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, Berlin, Germany
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- Weiss, Manfred S. (author)
- Macromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, Berlin, Germany,Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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- Robertson, Angus (author)
- NIH, LCP NIDDK, MD, Bethesda, United States
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- Bax, Adriaan (author)
- NIH, LCP NIDDK, MD, Bethesda, United States
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Sreeramulu, Sridhar (author)
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- Schwalbe, Harald (author)
- Institute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany; Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany
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(creator_code:org_t)
- American Chemical Society (ACS), 2024
- 2024
- English.
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In: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 19:2, s. 563-574
- Related links:
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://doi.org/10.1...
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Abstract
Subject headings
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- The main protease Mpro, nsp5, of SARS-CoV-2 (SCoV2) is one of its most attractive drug targets. Here, we report primary screening data using nuclear magnetic resonance spectroscopy (NMR) of four different libraries and detailed follow-up synthesis on the promising uracil-containing fragment Z604 derived from these libraries. Z604 shows time-dependent binding. Its inhibitory effect is sensitive to reducing conditions. Starting with Z604, we synthesized and characterized 13 compounds designed by fragment growth strategies. Each compound was characterized by NMR and/or activity assays to investigate their interaction with Mpro. These investigations resulted in the four-armed compound 35b that binds directly to Mpro. 35b could be cocrystallized with Mpro revealing its noncovalent binding mode, which fills all four active site subpockets. Herein, we describe the NMR-derived fragment-to-hit pipeline and its application for the development of promising starting points for inhibitors of the main protease of SCoV2.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Altincekic, Nadi ...
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Jores, Nathalie
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Löhr, Frank
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Richter, Christi ...
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Ehrhardt, Claus
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Blommers, Marcel ...
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show more...
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Berg, Hannes
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Öztürk, Sare
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Gande, Santosh L ...
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Linhard, Verena
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Orts, Julien
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Abi Saad, Marie ...
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Bütikofer, Matth ...
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Kaderli, Janina
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Karlsson, B Göra ...
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Brath, Ulrika
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Hedenström, Matt ...
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Gröbner, Gerhard
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Sauer, Uwe H.
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Perrakis, Anasta ...
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Langer, Julian
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Banci, Lucia
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Cantini, Frances ...
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Fragai, Marco
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Grifagni, Debora ...
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Barthel, Tatjana
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Wollenhaupt, Jan
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Weiss, Manfred S ...
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Robertson, Angus
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Bax, Adriaan
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Sreeramulu, Srid ...
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Schwalbe, Harald
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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ACS Chemical Bio ...
- By the university
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University of Gothenburg
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Umeå University