Allopurinol widely used in gout treatment is the most common cause of severe cutaneous adverse drug reactions The risk of developing such life-threatening reactions is increased particularly for HLA

This passage discusses the relationship between allopurinol, a medication commonly used to treat gout, and severe cutaneous adverse drug reactions. It is mentioned that the risk of these reactions is higher for individuals who are positive for the HLA-B*58:01 gene. However, the mechanism by which allopurinol and HLA interact is still unknown.

The passage goes on to describe an experiment where a specific peptide called KAGQVVTI, which does not bind to HLA-B58:01 on its own, was found to form a stable complex with HLA-B58:01 only in the presence of allopurinol. Crystal structure analysis revealed that allopurinol caused the peptide to adopt an unconventional binding conformation, where the C-terminal isoleucine did not fit deeply in the binding F-pocket as expected.

Similar observations were made with another substance called oxypurinol, although to a lesser extent. The presentation of these unconventional peptides by HLA-B*58:01 with the help of allopurinol may contribute to our understanding of drug-HLA interactions. The binding of peptides from self-proteins like lamin A/C and viral proteins like EBNA3B in the presence of allopurinol suggests that the abnormal loading of unconventional peptides could potentially trigger harmful reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)