Photoisomerization of Azobenzene‐Extended Charybdotoxin for the Optical Control of K_v1.2 Potassium Channel Activity

Abstract Natural peptides from animal venoms effectively modulate ion channel activity. While photoswitches regulate small compound pharmacology, their application to natural peptides rich in disulfide bridges and active on ion channels is novel due to larger pharmacophores. A pilot study integrating azobenzene photoswitches into charybdotoxin (ChTx), known for blocking potassium channels is initiated. Two click‐chemistry‐compatible azobenzene are synthesized differing in length and amide orientation (Az 1 & Az 2 ). Az 1 is grafted onto ChTx at various amino acid positions using L‐azidohomoalanine mutation. ChTx monomers outperformed dimers, particularly with azobenzene at position 14, by exhibiting optimal photoswitching activity. In the cis configuration, Az 1 altered ChTx's pharmacophore, reducing potassium channel blockage, while conversely, Az 2 increased ChTx potency. This study pioneers photoswitch application to complex peptides, leveraging structure‐activity relationships. Successful integration depends on precise azobenzene positioning and chemical grafting guided by SAR insights. This advancement underscores the adaptability of photoswitch technology to intricate peptide structures, offering new avenues for pharmacological modulation.