Expedited SARS‐CoV‐2 main protease inhibitor discovery through modular 'direct‐to‐biology' screening
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Wilders, Harry and Biggs, George and Rowe, Sam M. and Cawood, Emma E. and Riziotis, Ioannis G. and Rendina, Alan R. and Grant, Emma K. and Pettinger, Jonathan and Fallon, David J. and Skehel, Mark and House, David and Tomkinson, Nicholas C. O. and Bush, Jacob T. (2024) Expedited SARS‐CoV‐2 main protease inhibitor discovery through modular 'direct‐to‐biology' screening. Angewandte Chemie. e202418314. ISSN 1521-3773 (https://doi.org/10.1002/ange.202418314)
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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 (MPro), 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 MPro 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.
ORCID iDs
Wilders, Harry, Biggs, George, Rowe, Sam M., Cawood, Emma E., Riziotis, Ioannis G., Rendina, Alan R., Grant, Emma K., Pettinger, Jonathan, Fallon, David J., Skehel, Mark, House, David, Tomkinson, Nicholas C. O.
ORCID: https://orcid.org/0000-0002-5509-0133 and Bush, Jacob T.;
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Item type: Article ID code: 91567 Dates: DateEvent10 December 2024Published10 December 2024Published Online4 December 2024Accepted23 September 2024SubmittedSubjects: Science > Chemistry Department: Faculty of Science > Pure and Applied Chemistry Depositing user: Pure Administrator Date deposited: 12 Dec 2024 17:30 Last modified: 18 Dec 2024 01:43 URI: https://strathprints.strath.ac.uk/id/eprint/91567