Allopurinol and HLA-B*58:01 Interaction: Unconventional Peptide Binding and the Risk of Severe Cutaneous Reactions

This passage explores the relationship between allopurinol, a medication widely used for gout treatment, and severe cutaneous adverse drug reactions. Individuals carrying the HLA-B*58:01 gene are at a heightened risk of developing these life-threatening reactions, but the underlying mechanism of action between allopurinol and HLA remains unclear.

The study reveals that a specific peptide, KAGQVVTI, which normally doesn't bind to HLA-B58:01, forms a stable complex with HLA-B58:01 only in the presence of allopurinol. Crystal structure analysis indicates that allopurinol enables the peptide to adopt an unconventional binding conformation. This means the C-terminal isoleucine, typically fitting deeply within the binding F-pocket, doesn't engage as expected. While less pronounced, similar observations were made with oxypurinol.

The study's findings provide insight into drug-HLA interactions, highlighting how allopurinol's influence on HLA-B*58:01 enables the presentation of unconventional peptides. The binding of peptides derived from both self-proteins like lamin A/C and viral proteins like EBNA3B in the presence of allopurinol suggests that this abnormal loading of unconventional peptides could contribute to the development of severe reactions like Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).