TY - JOUR
T1 - Targeting the Main Protease (Mpro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
AU - Altincekic, Nadide
AU - Jores, Nathalie
AU - Löhr, Frank
AU - Richter, Christian
AU - Ehrhardt, Claus
AU - Blommers, Marcel J J
AU - Berg, Hannes
AU - Öztürk, Sare
AU - Gande, Santosh L
AU - Linhard, Verena
AU - Orts, Julien
AU - Abi Saad, Marie Jose
AU - Bütikofer, Matthias
AU - Kaderli, Janina
AU - Karlsson, B Göran
AU - Brath, Ulrika
AU - Hedenström, Mattias
AU - Sauer, Uwe H
AU - Perrakis, Anastassis
AU - Langer, Julian
AU - Banci, Lucia
AU - Cantini, Francesca
AU - Fragai, Marco
AU - Grifagni, Deborah
AU - Barthel, Tatjana
AU - Wollenhaupt, Jan
AU - Robertson, Angus
AU - Bax, Adriaan
AU - Sreeramulu, Sridhar
AU - Schwalbe, Harald
N1 - Publisher Copyright:
© 2024 The Authors. Published by American Chemical Society.
PY - 2024/2/16
Y1 - 2024/2/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85183508732&partnerID=8YFLogxK
U2 - 10.1021/acschembio.3c00720
DO - 10.1021/acschembio.3c00720
M3 - Article
C2 - 38232960
SN - 1554-8929
VL - 19
SP - 563
EP - 574
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 2
ER -