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+ (Nav) channel is the
molecular determinant of excitability. Disruption of protein–protein
interactions (PPIs) between Nav1.6 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:Nav1.6 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 Nav1.6. Whole-cell
patch-clamp electrophysiology subsequently revealed that 21a had functionally relevant interactions with both the C-terminal
tail of Nav1.6 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.