Design, Synthesis, and Pharmacological Evaluation of Analogues Derived from the PLEV Tetrapeptide as Protein–Protein Interaction Modulators of Voltage-Gated Sodium Channel 1.6

The voltage-gated Na⁺ (Na_v) channel is the molecular determinant of excitability. Disruption of protein–protein interactions (PPIs) between Na_v1.6 and fibroblast growth factor 14 (FGF14) leads to impaired excitability of neurons in clinically relevant brain areas associated with channelopathies. Here, we designed, synthesized, and pharmacologically characterized new peptidomimetics based on a PLEV tetrapeptide scaffold derived from the FGF14:Na_v1.6 PPI interface. Addition of an N-terminal 1-adamantanecarbonyl pharmacophore significantly improved peptidomimetic inhibitory potency. Surface plasmon resonance studies revealed that while this moiety was sufficient to confer binding to FGF14, altering the C-terminal moiety from methoxy (21a) to π bond-containing (23a and 23b) or cycloalkane substituents (23e) abrogated the binding to Na_v1.6. Whole-cell patch-clamp electrophysiology subsequently revealed that 21a had functionally relevant interactions with both the C-terminal tail of Na_v1.6 and FGF14. Collectively, these findings support that 21a (PW0564) may serve as a promising lead to develop target-selective neurotherapeutics by modulating protein–channel interactions.