Project Title

Structure-based improved treatments for atrial fibrillation

Background

AF is the cause of 1/3 of all hospitalized heart rhythm disturbances and is associated with an increased risk of stroke & heart failure. Current treatments include anti-arrhythmic drugs and ablation, however, these have significant limitations, e.g. high risk for adverse events, high costs and low efficacy. SK-channels display a different expression profile and directly influence the action potential of the heart. Novel drugs targeting SK-channels could avoid serious side effects.

Aim

The specific aims are to:

• Determine the first structure of a human SK-channel using cryo-EM to shed light on its molecular function
• Obtain a high-resolution structure of SK-channel in complex AF-modulator(s)
• Commence structure-based drug-optimization efforts including preclinical validation

Methods

Using cryo-EM to determine the high-resolution structure of at least one SK-channel apo structure and with modulator bound will be the first key milestone. Next, we will design and synthesize new small molecules based on structural input in collaboration with Acesion Pharma. Their effect will be evaluated with patch clamp on HEK cells and later the SK-channels will be reconstituted into liposomes.

Preliminary results

So far, sufficient amounts of full-length human SK1 channel has been purified from yeast cells, providing a promising foundation for solving the protein structure. The fluorescence-detection size exclusion chromatography profile is indicative of a well-behaved channel. Recently, pharmacological inhibition of SK‐channels with AP14145 in a porcine model has been shown to prevent atrial arrhythmogenic changes.