A Nucleophilic Chemical Probe Targeting Electrophilic Functional Groups in an Untargeted Way to Explore Cysteine Modulators in Natural Products

The
vital roles of biologically relevant cysteines have been discovered
from proteins that are promising targets for new drugs or chemical
tools. Therefore, new electrophilic small molecules that can covalently
modulate these cysteines have attracted immense interest. Because
of their extremely wide chemical diversity, electrophilic natural
products (NPs) have been studied as promising sources of cysteine
modulators. Previous studies have developed chemical probes to facilitate
the detection and isolation of electrophilic NPs. To address the problems
with the current methods, including their low sensitivity, high false-positive
rate, and dependence on performing manual processing with a plethora
of spectra, we report a chemical probe that can first covalently capture
electrophilic NPs from natural resources and then produce sensitive
reporter ion signals that are specific for the detected NPs. We applied
this untargeted method to explore electrophilic NPs from natural resources
and found that the complexity of electrophilic NPs was beyond our
expectations. We used this chemical probe to identify a new electrophilic
furanosesterterpene (BG-1) from an extract of Ginkgo biloba that targets the Cys207 of acyl-CoA
thioesterase 7 (ACOT7).