Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
- Author(s)
- Nadide Altincekic, Nathalie Jores, Frank Löhr, Christian Richter, Claus Ehrhardt, Marcel J J Blommers, Hannes Berg, Sare Öztürk, Santosh L Gande, Verena Linhard, Julien Orts, Marie Jose Abi Saad, Matthias Bütikofer, Janina Kaderli, B Göran Karlsson, Ulrika Brath, Mattias Hedenström, Uwe H Sauer, Anastassis Perrakis, Julian Langer, Lucia Banci, Francesca Cantini, Marco Fragai, Deborah Grifagni, Tatjana Barthel, Jan Wollenhaupt, Angus Robertson, Adriaan Bax, Sridhar Sreeramulu, Harald Schwalbe
- Abstract
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.
- Organisation(s)
- Department of Pharmaceutical Sciences
- External organisation(s)
- Johann Wolfgang Goethe-Universität Frankfurt am Main, Eidgenössische Technische Hochschule Zürich, SavernaTherapeutics, University of Gothenburg, Umeå University, Netherlands Cancer Institute, Max-Planck-Institut für Biophysik, University of Florence, Helmholtz-Zentrum Berlin für Materialien und Energie, National Institutes of Health (NIH), Consorzio Interuniversitario Risonanze Magnetiche Metalloproteine
- Journal
- ACS Chemical Biology
- Volume
- 19
- Pages
- 563-574
- No. of pages
- 12
- ISSN
- 1554-8929
- DOI
- https://doi.org/10.1021/acschembio.3c00720
- Publication date
- 01-2024
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 106006 Biophysics, 104026 Spectroscopy, 301207 Pharmaceutical chemistry
- ASJC Scopus subject areas
- Molecular Medicine, Biochemistry
- Portal url
- https://ucris.univie.ac.at/portal/en/publications/targeting-the-main-protease-mpro-nsp5-by-growth-of-fragment-scaffolds-exploiting-structurebased-methodologies(4c720320-9324-4228-ace0-e8c1ad430058).html