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40 reviewsSUMMARYIon channels orchestrate electrical signaling in excitable cells. In nature, ion channel function is customizedby modulatory proteins that have evolved to fulfill distinct physiological needs. Yet, engineering syntheticmodulators that precisely tune ion channel function is challenging. One example involves the voltage-gatedsodium (NaV) channel that initiates the action potential and whose dysfunction amplifies the late/persistentsodium current (INaL), a commonality that underlies various human diseases, including cardiac arrhythmiasand epilepsy. Here, using a computational protein design platform, we engineered a de novo peptide modulator, engineered late-current inhibitor X by inactivation-gate release (ELIXIR), that binds NaV channels withsubmicromolar affinity. Functional analysis revealed unexpected selectivity in inhibiting ‘‘pathogenic’’ INaLand confirmed its effectiveness in reversing NaV dysfunction linked to both cardiac arrhythmias and epilepsyin cellular and murine models. These findings exemplify the efficacy of de novo protein design for engineeringsynthetic ion channel modulators and set the stage for the rational design of future therapeutic approaches.
