Animal venom peptides like charybdotoxin (ChTx) are known for their high specificity and potency as potassium channel blockers, making them valuable tools in ion channel research. However, achieving precise spatial and temporal control over their activity remains challenging. While photoswitchable small molecules have been successfully developed, incorporating such technology into larger peptides has been hindered by structural complexity and folding challenges.

In a recent study, a research group led by Michel De Waard addressed this issue by integrating photo-switchable azobenzene groups (Az1 and Az2) into ChTx via click chemistry, creating peptides whose activity can be controlled with light. They strategically mutated residues outside ChTx’s critical pharmacophore to incorporate the azobenzene groups post-folding, preserving the peptide’s essential structural integrity and biological potency.

Electrophysiological recordings using SyncroPatch 384, demonstrated successful modulation of Kv1.2 potassium channel activity by these engineered peptides.

Interestingly, Az1 and Az2 exhibited opposite effects upon switching to the cis (UV-activated) conformation: Az1 reduced ChTx potency, whereas Az2 substantially enhanced it. Structural analysis via NMR spectroscopy confirmed that these potency changes result from specific conformational shifts that reposition critical pharmacophore residues.

This study is the first to successfully integrate photoswitch technology into a complex, disulfide-rich peptide while retaining high nanomolar potency for ion channels. It demonstrates that natural peptides can be adapted for precise, reversible optical control of ion channels, opening new avenues for optically tunable peptide-based tools with promising implications for both fundamental research and therapeutic innovation targeting ion channels.

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Find the full article here: Photo-isomerization of azobenzene-extended charybdotoxin for the optical control of Kv1.2 potassium channel activity

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