Protein expression is not directly linked to activity, which is often regulated by post-transcriptional modifications. To address this challenge, activity-based probes (ABPs) have been developed to functionally profile hundreds to thousands of protein targets (i.e. chemoproteomic analyses). ABPs are composed of two major components: a reactive ‘warhead’ and a reporter tag. The warhead covalently, and irreversibly, modifies protein binding sites in a mechanism-dependent manner. The reporter tag permits detection of probe modified proteins by fluorescent visual detection in SDS-PAGE assays, or detection of small molecule binding sites through mass spectrometry sequencing and quantification of enriched peptides. The resulting binding profiles can lead to new biological insights, and furnish lead compounds for developing selective inhibitors against diverse protein families. ABPs selectively label proteins in active conformations, providing advantages over traditional biochemical techniques like western blotting, which is limited to detecting protein abundance. Furthermore, ABPs can measure protein function directly in lysates, live cells, and even in animal models. The ability to study proteins in complex cellular environments is crucial because proteins do not work in isolation, but instead function with binding partners as part of complex biochemical pathways. While ABP development has furnished chemical probes for numerous protein families, the number of validated ABPs is severely lacking compared with the diversity of the human proteome. Our goal has been to expand chemical probes available to study protein function by exploring azetidines as novel ABPs, which we recently discovered to react with proteins through cysteine residues via a novel ring-opening mechanism.

Uncovering the chemoproteomic potential of azetidines

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.