efsevin

Efsevin is a synthetic small molecule that acts as a potent agonist and gating modifier of the voltage-dependent anion channel 2 (VDAC2) located in the outer mitochondrial membrane. Originally identified through a chemical suppressor screen in zebrafish embryos with calcium extrusion defects, efsevin binds to a specific pocket formed by the inner channel wall and the pore-lining N-terminal α-helix of VDAC2. This binding shifts the channel's open probability toward states that facilitate enhanced mitochondrial calcium (Ca2+) uptake and accelerates the transfer of Ca2+ from the sarcoplasmic reticulum to the mitochondria. By restricting the spatial and temporal boundaries of Ca2+ sparks, efsevin inhibits the formation of arrhythmogenic diastolic Ca2+ waves and restores coordinated cardiac contractions. Preclinical studies have demonstrated its potential as an antiarrhythmic therapy for conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT) and as a treatment for heart failure by improving cardiac contractile force.