Fluoromethylketone-Fragment Conjugates Designed as Covalent Modifiers of EcDsbA are Atypical Substrates.
ChemMedChem
; 19(16): e202300684, 2024 Aug 19.
Article
in En
| MEDLINE
| ID: mdl-38742480
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 (EcDsbA) is essential for bacterial virulence, thus inhibitors have the potential to act as antivirulence agents. A fragment-based screen was conducted against EcDsbA 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 EcDsbA, 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Escherichia coli Proteins
/
Escherichia coli
/
Ketones
Language:
En
Journal:
ChemMedChem
/
ChemMedChem (Internet)
Journal subject:
FARMACOLOGIA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
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