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Journal/Book: ACS Chem Biol
Published: 2024
Accession no.:

Targeting main protease (Mpro, nsp5) by growth of fragment scaffolds exploiting structure-based methodologies.

N. Altincekic, N. Jores, F. Löhr, C. Richter, C. Ehrhardt, M.J.J. Blommers, H. Berg, S. Öztürk, S.L. Gande, V. Linhard, J. Orts, M.J. Abi Saad, M. Bütikofer, J. Karderli, B.G. Karlsson, U. Brath, M. Hedenström, G. Gröbner, U.H. Sauer, A. Perrakis, J. Langer, L. Banci, F. Cantini, M. Fragai, D. Grifagni, T. Barthel, Jan Wollenhaupt, M.S. Weiss, A. Robertson, Adriaan Bax, S. Sreeramulu, H. Schwalbe
The main protease Mpro, nsp5 of the 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 the 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 by 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 co-crystalized with Mpro revealing its non-covalent binding mode, which fills all four active site sub-pockets. 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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© Copyright 2024
Prof. Dr. Harald Schwalbe
Institut für Organische Chemie und Chemische Biologie
Johann Wolfgang Goethe Universität
Max-von-Laue-Str. 7
D-60438 Frankfurt am Main
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