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Targeting the main protease (Mpro, nsp5) by growth of fragment scaffolds exploiting structure-based methodologies
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.
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.
Center of Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt am Main, Frankfurt, Germany; Institute of Biophysical Chemistry, Goethe University Frankfurt am Main, Frankfurt, 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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2024 (Engelska)Ingår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 19, nr 2, s. 563-574Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

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American Chemical Society (ACS), 2024. Vol. 19, nr 2, s. 563-574
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-220471DOI: 10.1021/acschembio.3c00720ISI: 001162216100001PubMedID: 38232960Scopus ID: 2-s2.0-85183508732OAI: oai:DiVA.org:umu-220471DiVA, id: diva2:1838232
Forskningsfinansiär
EU, Horisont 2020, 871037EU, Horisont 2020, 101094131Science for Life Laboratory, SciLifeLabKnut och Alice Wallenbergs Stiftelse, 2020.0182Tillgänglig från: 2024-02-15 Skapad: 2024-02-15 Senast uppdaterad: 2024-05-08Bibliografiskt granskad

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Hedenström, MattiasGröbner, GerhardSauer, Uwe H.

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