Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target's perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low-throughput, constrained by the need for synthesis and purification of target compounds. We report an efficient platform for 'direct-to-biology' (D2B) screening of cysteine-targeting chloroacetamide RFs, wherein synthesis is performed in 384-well plates allowing direct assessment in downstream biological assays without purification. Here, the developed platform was used to optimise inhibitors of SARS-CoV-2 main protease (M<sup>Pro</sup>), an established drug target for the treatment of COVID-19. An initial RF hit was developed into a series of potent inhibitors, and further exploration using D2B screening enabled a 'switch' to a reversible inhibitor series. This example of ligand discovery for M<sup>Pro</sup> illustrates the acceleration that D2B chemistry can offer for optimising RFs towards covalent inhibitor candidates, as well as providing future impetus to explore the evolution of RFs into non-covalent ligands.

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Publication Details

Journal
Angewandte Chemie International Edition
Published
2024-12-04
DOI
https://doi.org/10.1002/anie.202418314
Citations
12
Primary Topic
Click Chemistry and Applications
Type
article
Field-Weighted Citation Impact
3.00

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article

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Alan R. Rendina, Emma E. Cawood, Sam M. Rowe, Mark Skehel et al.
12 citations
Angewandte Chemie International Edition
Click Chemistry and Applications
3.00
article

Expedited SARS‐CoV‐2 Main Protease Inhibitor Discovery through Modular ‘Direct‐to‐Biology’ Screening

Alan R. Rendina, Emma E. Cawood, Sam M. Rowe, Mark Skehel, David House, George S. Biggs, Ioannis G. Riziotis, Jacob T. Bush, Nicholas C. O. Tomkinson, Emma K. Grant, Jonathan Pettinger, David J. Fallon, Harry Wilders
article en
12 citations

Abstract

Reactive fragment (RF) screening has emerged as an efficient method for ligand discovery across the proteome, irrespective of a target's perceived tractability. To date, however, the efficiency of subsequent optimisation campaigns has largely been low-throughput, constrained by the need for synthesis and purification of target compounds. We report an efficient platform for 'direct-to-biology' (D2B) screening of cysteine-targeting chloroacetamide RFs, wherein synthesis is performed in 384-well plates allowing direct assessment in downstream biological assays without purification. Here, the developed platform was used to optimise inhibitors of SARS-CoV-2 main protease (M<sup>Pro</sup>), an established drug target for the treatment of COVID-19. An initial RF hit was developed into a series of potent inhibitors, and further exploration using D2B screening enabled a 'switch' to a reversible inhibitor series. This example of ligand discovery for M<sup>Pro</sup> illustrates the acceleration that D2B chemistry can offer for optimising RFs towards covalent inhibitor candidates, as well as providing future impetus to explore the evolution of RFs into non-covalent ligands.

Angewandte Chemie International EditionVol. 64(6)
University of Strathclyde (GB), Age UK (GB), The Francis Crick Institute (GB), South College (US), North Hertfordshire College (GB), GlaxoSmithKline (Ireland) (IE)
Wellcome Trust, Francis Crick Institute, Cancer Research UK, Medical Research Council, Engineering and Physical Sciences Research Council
Good health and well-being
Openalex Percentile: Top 8%
Click Chemistry and Applications
3.00
DOIOpen Access PDFOpenAlex
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