Abstract
Sulfur electrophiles constitute an important class of covalent small molecules that have found widespread applications in synthetic chemistry and chemical biology. Various electrophilic scaffolds, including sulfonyl fluorides and arylfluorosulfates as recent examples, have been applied for protein bioconjugation to probe ligand sites amenable for chemical proteomics and drug discovery. In this review, we describe the development of sulfonyl-triazoles as a new class of electrophiles for sulfur–triazole exchange (SuTEx) chemistry. SuTEx achieves covalent reaction with protein sites through irreversible modification of a residue with an adduct group (AG) upon departure of a leaving group (LG). A principal differentiator of SuTEx from other chemotypes is the selection of a triazole heterocycle as the LG, which introduces additional capabilities for tuning the sulfur electrophile. We describe the opportunities afforded by modifications to the LG and AG alone or in tandem to facilitate nucleophilic substitution reactions at the SO2 center in cell lysates and live cells. As a result of these features, SuTEx serves as an efficient platform for developing chemical probes with tunable bioactivity to study novel nucleophilic sites on established and poorly annotated protein targets. Here, we highlight a suite of biological applications for the SuTEx electrophile and discuss future goals for this enabling covalent chemistry.
Highlights
Introduction a Department ofPharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USASmall molecule probes are enabling tools for understanding protein function in cells and tissues under healthy and diseased states.[1,2] Chemical probes offer a complementary approach to genetic methods for investigating biological pathways and testing therapeutic hypotheses.[3]
The sulfur–triazole exchange (SuTEx) electrophile has emerged as a versatile chemical biology tool that is well-suited for global investigations of tyrosines in protein functional sites
The findings to date have provided a glimpse of the potential for using this electrophile for chemical proteomic evaluation and pharmacological modulation of reactive tyrosines on proteins with functions ranging from enzyme chemistry to protein–protein and protein–nucleotide recognition
Summary
Development and biological applications of sulfur–triazole exchange (SuTEx) chemistry. Sulfur electrophiles constitute an important class of covalent small molecules that have found widespread applications in synthetic chemistry and chemical biology. We describe the development of sulfonyl-triazoles as a new class of electrophiles for sulfur–triazole exchange (SuTEx) chemistry. As a result of these features, SuTEx serves as an efficient platform for developing chemical probes with tunable bioactivity to study novel nucleophilic sites on established and poorly annotated protein targets. We highlight a suite of biological applications for the SuTEx electrophile and discuss future goals for this enabling covalent chemistry. These tools can reveal pharmacological effects of protein modulation that are rapid, reversible, and universal with respect to sample type.[1]
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