Ekaterina Vinogradova

An activity-guided map of electrophile-cysteine interactions in primary human immune cells

Despite major advances in our understanding of the genetic basis of human immune disorders, the majority of immune-relevant proteins lack chemical probes to facilitate their functional characterization and streamline future drug development programs. In this presentation, I will describe how recognizing the profound immunomodulatory effects displayed by electrophilic compounds, we have employed an innovative chemical proteomic platform to generate the first global portrait of cysteine reactivity and druggability in the human immune proteome. I will further talk about the pharmacological effects and tractability of small molecule-cysteine interactions uncovered by deploying chemically elaborated electrophiles combined with a functional screen of T cell activation. This integrated chemical proteomic and phenotypic screening approach uncovered immunomodulatory compounds that act by diverse mechanisms, including the direct inhibition of protein activity and induction of protein degradation. These findings reveal a rich content of ligandable cysteines in human T cells, underscoring the broad potential for electrophilic compounds to expand the druggability of the human immune proteome for both basic and translational research purposes.