Title: Cysteine-reactive electrophilic compounds remodel the proteome by modulating cellular proteostasis processes

Covalent compounds and the related covalent degrader molecules have emerged as a drug modality that offers tremendous therapeutic potential for targeting tough-to-drug classes of proteins. Here I will discuss our discovery of a cysteine-reactive small molecule degrader of the SARS-CoV-2 non-structural protein 14 (nsp14), which effects degradation through direct modification of cysteines in both nsp14 and in host chaperones, together with activation of global cell stress response pathways. We find that cysteine-reactive electrophiles increase global protein ubiquitylation, trigger proteasome activation, and result in widespread aggregation and depletion of host proteins, including components of the nuclear pore complex. Formation of stress granules was also found to be a remarkably ubiquitous cellular response to nearly all cysteine-reactive compounds and degraders evaluated. By shedding light on heretofore underappreciated complexities of cysteine-reactive covalent compound behavior in cells, I will also put forth the roadmap of best practices going forward for the field of cysteine chemoproteomics to ensure on-target modes-of-action and also highlights new opportunities for delineating how covalent compounds modulate proteostasis processes.