Host reactive cysteinome

Host cell proteins with reactive cysteine residues, collectively known as the host reactive cysteinome, represent a diverse subset of the human proteome characterized by nucleophilic cysteine thiols that are susceptible to covalent modification by electrophilic small molecules. This group includes a wide range of functional proteins such as kinases (e.g., BTK, EGFR), proteases (e.g., Cathepsins), and transcription factors (e.g., KEAP1), where the reactive cysteine often plays a critical role in catalysis or regulation. In drug discovery, these residues are targeted by covalent inhibitors to achieve high potency, selectivity, and a prolonged duration of action through the formation of permanent chemical bonds. For example, dimethyl fumarate targets reactive cysteines in KEAP1 and GAPDH to modulate antioxidant and inflammatory pathways in diseases like multiple sclerosis. Furthermore, targeting host cell proteins with reactive cysteines is an emerging strategy for developing host-directed antivirals, as it can disrupt viral replication cycles by inhibiting essential host factors while minimizing the risk of viral resistance. However, the therapeutic use of covalent drugs targeting these residues requires careful design to avoid off-target reactivity and potential immunogenic responses resulting from protein-drug adduct formation.

Other names

Host reactive cysteinomeLigandable cysteinesCysteine proteomeReactive cysteinomeNucleophilic cysteines

Covalent modification of nucleophilic cysteine thiols via Michael addition, alkylation, or other electrophilic reactions