Mapping context sensitive properties of Kv channels to improve selective drug design

Current treatments do not provide sufficient relief for up to 30% of those suffering from excitability conditions such as cardiac arrhythmias and epilepsy.

Voltage-gated potassium (Kv) channels are critical for regulating cellular excitability and promising new pharmacological targets.

However, the human genome encodes many Kv channels with similar overall sequence and structure, hampering development of safe drugs targeting only relevant Kv channels.

This project explores an innovative approach to address this problem utilizing frontline experimental and computational approaches and using the human Kv7 family (strongly linked to pathology and sudden death) as a prototype.

Preliminary data suggest that post-translational modifications and the local lipid molecular habitat alter Kv7 pharmacology in a subtype selective manner, which is why this project seeks to: (i) identify endogenous factors that contribute structural diversity to Kv7 channels beyond the protein coding sequence (referred to as ‘selectifiers’), (ii) develop a conceptually new pharmaceutical strategy by designing drugs that target druggable pockets and mechanisms revealed by selectifiers, and (iii) provide proof of concept of efficient and selective effects of developed compounds.

This project will provide insights into how endogenous factors establish channel diversity and open up new avenues for selective drug development, ultimately improving the clinical outcome for conditions of abnormal excitability.