Protein thiol residues (Protein-SH)

Protein thiol residues, primarily the sulfhydryl groups of cysteine, function as essential redox-sensitive switches and catalytic sites within various immune cell proteins and enzymes (Jacob et al., 2011, https://doi.org/10.1039/C0CS00031F). These nucleophilic moieties are the primary targets for electrophilic therapeutic agents, which modify them through covalent interactions such as Michael addition to modulate cellular signaling (Liby & Sporn, 2012, https://doi.org/10.1038/nrc3238). In the context of immunology, the modification of thiols on proteins like Keap1 leads to the stabilization of Nrf2, promoting an antioxidant and anti-inflammatory response (Linker et al., 2011, https://doi.org/10.1016/S0140-6736(10)62110-1). Conversely, the inhibition of thiols on enzymes like GAPDH or IKK-beta can suppress glycolytic flux and pro-inflammatory NF-kB signaling, respectively (Kornberg et al., 2018, https://doi.org/10.1126/science.aap7513). Drugs such as dimethyl fumarate and bardoxolone methyl leverage this reactivity to treat autoimmune and inflammatory conditions. However, the ubiquitous nature of protein thiols poses a risk for off-target effects and the formation of immunogenic haptens, necessitating careful drug design to achieve specificity (Chipinda et al., 2011, https://doi.org/10.3390/molecules16086978).

Other names

Protein sulfhydryl groupsReactive cysteine residuesCysteine thiolsProtein-bound thiolsNucleophilic protein thiols

Drugs typically interact with protein thiol residues through covalent modification, most commonly via Michael addition or S-alkylation. This modification can lead to the inhibition of enzyme activity, alteration of protein-protein interactions, or the activation of cytoprotective pathways such as the Nrf2-mediated antioxidant response by modifying inhibitory proteins like Keap1.