A druggable redox switch on SHP1 controls macrophage inflammation

Immunological proteins are major disease targets and the majority remain undrugged. Post-translational redox modification of protein cysteine residues has emerged as a mode of immune cell regulation, especially in the context of the macrophage cytokine response.1 Here, we develop a strategy for systematic discovery and small molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 cysteines across diverse functional domains of immune-relevant proteins that are redox regulated in vivo. We demonstrate how these sites can be exploited to develop cysteine-directed pharmacology, exemplified by a newfound cysteine activation site on the core immunological regulator SHP1. By targeting Cys102 on SHP1, we develop a highly selective covalent SHP1 agonist, SCA. SCA binding to Cys102 in the N-terminal Src Homology 2 (N-SH2) domain promotes its rearrangement to relieve auto-inhibition and drive SHP1 activation. In macrophages and in vivo, SCA and its analogues rapidly and selectively engage SHP1 Cys102 and antagonize IL-1 Receptor-Associated Kinase signaling, pro-inflammatory cytokine production, and lipopolysaccharide (LPS)-induced sepsis in mice. Together, we discover a druggable cysteine redox switch controlling the macrophage cytokine response and provide a compendium of functionally annotated redox regulated sites for cysteine-directed therapeutics development.