Fluoromethylketone‐Fragment Conjugates Designed as Covalent Modifiers of Ec DsbA are Atypical Substrates

Abstract Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram‐negative bacteria. In Escherichia coli , DsbA ( Ec DsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment‐ba...

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Bibliographic Details
Published in:ChemMedChem 2024-08, Vol.19 (16)
Main Authors: Doak, Bradley C., Whitehouse, Rebecca L., Rimmer, Kieran, Williams, Martin, Heras, Begoña, Caria, Sofia, Ilyichova, Olga, Vazirani, Mansha, Mohanty, Biswaranjan, Harper, Jason B., Scanlon, Martin J., Simpson, Jamie S.
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Language:English
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Summary:Abstract Disulfide bond protein A (DsbA) is an oxidoreductase enzyme that catalyzes the formation of disulfide bonds in Gram‐negative bacteria. In Escherichia coli , DsbA ( Ec DsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment‐based screen was conducted against Ec DsbA and herein we describe the development of a series of compounds based on a phenylthiophene hit identified from the screen. A novel thiol reactive and “clickable” ethynylfluoromethylketone was designed for reaction with azide‐functionalized fragments to enable rapid and versatile attachment to a range of fragments. The resulting fluoromethylketone conjugates showed selectivity for reaction with the active site thiol of Ec DsbA, however unexpectedly, turnover of the covalent adduct was observed. A mechanism for this turnover was investigated and proposed which may have wider ramifications for covalent reactions with dithiol‐disulfide oxidoreducatases.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202300684