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Chemists use activity-based protein profiling (ABPP) to look for functional enzymes with specific activities, sometimes in hopes of finding leads for drug development. They search for these enzymes with molecules that form covalent bonds with amino acids in enzyme active sites. This method has focused on nucleophilic sites because no common amino acids have electrophilic side chains. But proteins can acquire electron-deficient sites via posttranslational modifications or electrophilic cofactors.
A new set of probes could allow chemists to start to apply ABPP to electrophilic sites, expanding the range of protein environments researchers can explore.
Last year, Megan L. Matthews of the University of Pennsylvania and coworkers reported that hydrazine probes could snag electrophilic sites in various enzyme classes (ACS Cent. Sci. 2021, DOI: acscentsci.1c00616). “It turns out that hydrazines react with and inhibit any enzyme that is electron deficient,” Matthews says. Although they uncovered interesting chemistry with these hydrazine probes, the molecules weren’t selective, which is a necessary feature for an ABPP probe.
So Matthews and coworkers set out to improve the selectivity of the hydrazine probes. Xie Wang, a postdoc in Matthews’s group, assembled a small library of hydrazine probes (most active one shown), including three based on approved drugs. The researchers found that simple tweaks can turn the hydrazine probes into potent and selective inhibitors (J. Am. Chem. Soc. DOI: 10.1021/jacs.1c12748). The findings suggest that the hydrazine drugs could be made safer and more effective, possibly with fewer side effects, Matthews says.
By alkylating the hydrazines at different positions and by tuning the molecules’ reactivity, the researchers introduced selectivity to the probes, preventing some interactions and promoting others. Even with a library of only 20 members, the team could selectively target secernin-3 (SCRN3) relative to the related secernin-2, both of which have glyoxylyl modifications.
“This ABPP platform for electrophiles is an innovative departure from traditional covalent libraries in the field that target nucleophilic sites like cysteine or lysine,” says Christopher J. Chang, a chemical biologist at the University of California, Berkeley.
“Although still at an early stage of development, this methodology has promise similar in importance to that of nucleophilic activity-based protein profiling,” says Richard B. Silverman, a chemistry professor at Northwestern University who was involved in the development of hydrazine drugs.
Matthews plans to use the selective inhibitors to characterize the activity of SCRN3, which she says may be a target for treatment of pain. She has also founded a company, Zenagem, to develop the probes for drug screening.
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