posted on 2024-01-18, 01:07authored byNadide 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, Gerhard Gröbner, Uwe H. Sauer, Anastassis Perrakis, Julian Langer, Lucia Banci, Francesca Cantini, Marco Fragai, Deborah Grifagni, Tatjana Barthel, Jan Wollenhaupt, Manfred S. Weiss, Angus Robertson, Adriaan Bax, Sridhar Sreeramulu, Harald Schwalbe
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.