7 research outputs found
Targeting Protein:Protein Interaction Sites for Drug Development against Voltage-Gated Sodium Channels
Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic
Protein–protein
interactions (PPI) offer unexploited opportunities
for CNS drug discovery and neurochemical probe development. Here,
we present ZL181, a novel peptidomimetic targeting the PPI interface
of the voltage-gated Na<sup>+</sup> channel Nav1.6 and its regulatory
protein fibroblast growth factor 14 (FGF14). ZL181 binds to FGF14
and inhibits its interaction with the Nav1.6 channel C-tail. In HEK-Nav1.6
expressing cells, ZL181 acts synergistically with FGF14 to suppress
Nav1.6 current density and to slow kinetics of fast inactivation,
but antagonizes FGF14 modulation of steady-state inactivation that
is regulated by the N-terminal tail of the protein. In medium spiny
neurons in the nucleus accumbens, ZL181 suppresses excitability by
a mechanism that is dependent upon expression of FGF14 and is consistent
with a state-dependent inhibition of FGF14. Overall, ZL181 and derivatives
could lay the ground for developing allosteric modulators of Nav channels
that are of interest for a broad range of CNS disorders
Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic
Protein–protein
interactions (PPI) offer unexploited opportunities
for CNS drug discovery and neurochemical probe development. Here,
we present ZL181, a novel peptidomimetic targeting the PPI interface
of the voltage-gated Na<sup>+</sup> channel Nav1.6 and its regulatory
protein fibroblast growth factor 14 (FGF14). ZL181 binds to FGF14
and inhibits its interaction with the Nav1.6 channel C-tail. In HEK-Nav1.6
expressing cells, ZL181 acts synergistically with FGF14 to suppress
Nav1.6 current density and to slow kinetics of fast inactivation,
but antagonizes FGF14 modulation of steady-state inactivation that
is regulated by the N-terminal tail of the protein. In medium spiny
neurons in the nucleus accumbens, ZL181 suppresses excitability by
a mechanism that is dependent upon expression of FGF14 and is consistent
with a state-dependent inhibition of FGF14. Overall, ZL181 and derivatives
could lay the ground for developing allosteric modulators of Nav channels
that are of interest for a broad range of CNS disorders