Targeting the Main Protease (M^pro, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies.

ABSTRACT: The main protease M^pro, 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 M^pro. These investigations resulted in the four-armed compound 35b that binds directly to M^pro. 35b could be cocrystallized wi

SUBMITTER: Altincekic N 

PROVIDER: S-EPMC10877576 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature