Targeting the Main Protease (Mᵖʳᵒ, nsp5) by Growth of Fragment Scaffolds Exploiting Structure-Based Methodologies
OPEN ACCESS
Author / Producer
Date
2024-02-16
Publication Type
Journal Article
ETH Bibliography
yes
Citations
Altmetric
OPEN ACCESS
Data
Rights / License
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 Mᵖʳᵒrevealing 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.
Permanent link
Publication status
published
External links
Editor
Book title
Journal / series
Volume
19 (2)
Pages / Article No.
563 - 574
Publisher
American Chemical Society
Event
Edition / version
Methods
Software
Geographic location
Date collected
Date created
Subject
Crystal cleavage; Inhibition; Ligands; Monomers; Peptides and proteins
Organisational unit
03782 - Riek, Roland / Riek, Roland
03713 - Sauer, Uwe / Sauer, Uwe
Notes
Funding
192646 - Exploring protein dynamics with atomic resolution (SNF)