Icatibant

Icatibant is a synthetic decapeptide antagonist of the bradykinin B2 receptor, originally developed by Hoechst under the code HOE 140. Its sequence is modelled on bradykinin but contains five non-proteinogenic amino acids, including D-arginine, hydroxyproline, thienylalanine, D-tetrahydroisoquinoline-3-carboxylic acid and octahydroindole-2-carboxylic acid. These substitutions confer resistance to kininases and turn an agonist template into a potent, selective antagonist.

Icatibant was approved in the EU in 2008 and by the FDA in 2011, marketed as Firazyr, for acute attacks of hereditary angioedema. Before its clinical development it was already a standard pharmacological tool: HOE 140 was used extensively from the early 1990s to define B2 receptor function in inflammation, pain, vascular permeability and cardiovascular physiology. Research continues into bradykinin-mediated angioedema beyond the hereditary form, including angioedema associated with ACE inhibitors, where trial results have been mixed. Icatibant is also a classic example of how non-natural residues can stabilise and repurpose a short peptide hormone.

Icatibant competitively blocks the bradykinin B2 receptor, a constitutively expressed Gq-coupled GPCR on endothelial cells, smooth muscle and sensory neurons. Bradykinin binding normally triggers nitric oxide and prostacyclin release, vasodilation and increased vascular permeability, as well as nociceptor sensitisation. In hereditary angioedema, deficient C1 esterase inhibitor activity allows excess bradykinin formation, and B2 receptor activation drives localised tissue swelling. Icatibant occupies the receptor without activating it, preventing these downstream effects. It has much lower affinity for the inducible B1 receptor, which responds to bradykinin metabolites and is studied separately in chronic inflammation research.