Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma.

The vasodilator hydralazine (HYZ) has been used clinically for ~ 70 years and remains on the World Health Organization's List of Essential Medicines as a therapy for preeclampsia. Despite its longstanding use and the concomitant progress toward a general understanding of vasodilation, the target and mechanism of HYZ have remained unknown. We show that HYZ selectively targets 2-aminoethanethiol dioxygenase (ADO) by chelating its metal cofactor and alkylating one of its ligands.

Discovery of Potent and Selective Inhibitors against Protein-Derived Electrophilic Cofactors.

Electrophilic cofactors are widely distributed in nature and play important roles in many physiological and disease processes, yet they have remained blind spots in traditional activity-based protein profiling (ABPP) approaches that target nucleophiles. More recently, reverse-polarity (RP)-ABPP using hydrazine probes identified an electrophilic -terminal glyoxylyl (Glox) group for the first time in secernin-3 (SCRN3). The biological function(s) of both the protein and Glox as a cofactor has not yet been pharmacologically validated because of the lack of selective inhibitors that could disrupt and therefore identify its activity.

Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets.

Most known probes for activity-based protein profiling (ABPP) use electrophilic groups that tag a single type of nucleophilic amino acid to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electrophilic enzyme cofactors, transient intermediates, and labile regulatory modifications, but ABPP probes for such species are underdeveloped. Here, we describe a versatile class of probes for this less charted hemisphere of the proteome.