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Targeting the Main ...
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Altincekic, NadideInstitute 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
(author)
Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
- Article/chapterEnglish2024
Publisher, publication year, extent ...
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American Chemical Society (ACS),2024
Numbers
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LIBRIS-ID:oai:gup.ub.gu.se/337303
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https://gup.ub.gu.se/publication/337303URI
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https://doi.org/10.1021/acschembio.3c00720DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-220471URI
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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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 and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Jores, NathalieInstitute 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
(author)
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Löhr, FrankCenter 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, ChristianInstitute 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, ClausDepartment of Biochemistry, University of Zurich, Zurich, Switzerland
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Blommers, Marcel J.J.SavernaTherapeutics, Biel-Benken, Switzerland
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Berg, HannesInstitute 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, SareInstitute for Organic Chemistry and Chemical Biology, Goethe University Frankfurt am Main, Frankfurt, Germany
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Gande, Santosh L.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, VerenaInstitute 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
(author)
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Orts, JulienDepartment of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria
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Abi Saad, Marie JoseDepartment of Pharmaceutical Sciences, University of Vienna, Josef-Holaubek-Platz 2, Vienna, Austria
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Bütikofer, MatthiasSwiss Federal Institute of Technology, Laboratory of Physical Chemistry, ETH Zurich, Zürich, Switzerland
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Kaderli, JaninaSwiss Federal Institute of Technology, Laboratory of Physical Chemistry, ETH Zurich, Zürich, Switzerland
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Karlsson, B Göran,1962Gothenburg 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(Swepub:gu)xkargo
(author)
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Brath, UlrikaGothenburg 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(Swepub:gu)xbraul
(author)
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Hedenström, Mattias,1976-Umeå universitet,Kemiska institutionen(Swepub:umu)mashem96
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Gröbner, GerhardUmeå universitet,Kemiska institutionen(Swepub:umu)gegr0001
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Sauer, Uwe H.Umeå universitet,Kemiska institutionen(Swepub:umu)uwsa0001
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Perrakis, AnastassisOncode Institute and Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, Netherlands
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Langer, JulianMax Planck Institute of Biophysics, Frankfurt am Main, Germany
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Banci, LuciaMagnetic 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
(author)
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Cantini, FrancescaMagnetic 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
(author)
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Fragai, MarcoMagnetic 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
(author)
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Grifagni, DeborahMagnetic Resonance Center and Department of Chemistry, University of Florence, Via L. Sacconi 6, Sesto Fiorentino, Italy
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Barthel, TatjanaMacromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, Berlin, Germany
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Wollenhaupt, JanMacromolecular Crystallography, Helmholtz-Zentrum Berlin, Albert-Einstein-Str. 15, Berlin, Germany
(author)
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Weiss, Manfred S.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
(author)
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Robertson, AngusNIH, LCP NIDDK, MD, Bethesda, United States
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Bax, AdriaanNIH, LCP NIDDK, MD, Bethesda, United States
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Sreeramulu, Sridhar
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Schwalbe, HaraldInstitute 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
(author)
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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, GermanyCenter of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany; Institute of Biophysical Chemistry, Goethe University Frankfurt am Main, Frankfurt, Germany
(creator_code:org_t)
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In:ACS Chemical Biology: American Chemical Society (ACS)19:2, s. 563-5741554-89291554-8937
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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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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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Umeå University