De novo Design of a Peptide Modulator to Reverse Sodium Channel Dysfunction Linked to Cardiac Arrhythmias and Epilepsy

Ion channels orchestrate electrical signaling in excitable cells. In nature, ion channel function is customized by modulatory proteins that have evolved to fulfill distinct physiological needs. Yet, engineering synthetic modulators that precisely tune ion channel function is challenging. One example involves the voltage-gated sodium (Na_V) channel that initiates the action potential, and whose dysfunction amplifies late/persistent sodium current (I_NaL), a commonality that underlies various human diseases including cardiac arrhythmias and epilepsy. Here, using a computational protein design platform, we engineered ade novopeptide modulator, ELIXIR, that binds Na_Vchannels with submicromolar affinity. Functional analysis revealed an unexpected selectivity in inhibiting ‘pathogenic’I_NaLand confirmed its effectiveness in reversing Na_Vdysfunction linked to both cardiac arrhythmias and epilepsy in cellular and murine models. These findings exemplify the efficacy ofde novoprotein design for engineering synthetic ion channel modulators and sets the stage for rational design of future therapeutic approaches.