Ligandability assessment of interferonopathy‐associated proteins using chemoproteomics

Mendelian type I interferonopathies are autoimmune diseases caused by genetic mutations that result in upregulation of interferon signalling. Small molecules that modulate proteins encoded by these genes may drive anti-tumour immunity in cancer patients by increasing interferon levels, but chemical probes and drugs are lacking. Covalent chemoproteomics and structural data were compiled to reveal ligandable cysteines, tyrosines and lysines across diverse proteins associated with interferonopathies. From this analysis, we identified several actionable targets, including ligandable sites on ADAR1, RNASEH2A and SAMHD1, and so our work provides a useful resource for future drug discovery efforts directed towards the development of immunotherapeutics.