Frontiers in Chemistry and Chemical Engineering

Cysteine is a unique amino acid, distinguished by its nucleophilicity and sensitivity to oxidative modifications. As a result of this privileged chemistry, cysteine-reactive molecules have emerged as high value tools for functional biology and drug development applications. Exemplifying the importance of these molecules, the recently FDA-approved drug Sotorasib functions by covalently modifying the Gly12Cys oncogenic form of KRAS, a protein long thought to be undruggable. Thus, there is widespread interest in the discovery of new ligandable (potentially druggable) and redox sensitive cysteine residues. Cysteine chemoproteomic platforms, including those from our group, are highly enabling technology increasingly used for the discovery of such high value cysteines. However, a key bottleneck in these pipelines is the absence of a priori insight into the likely functionality of identified cysteines. Here, I will present our group's innovative function-centric chemoproteomic platforms that are tailored to identify functional, redox sensitive, and therapeutically relevant cysteine residues. I will also discuss our ongoing efforts to delineate cysteine-specific drivers of stress granule formation.