TY - JOUR
T1 - Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic
AU - Ali, Syed R.
AU - Liu, Zhiqing
AU - Nenov, Miroslav N.
AU - Folorunso, Oluwarotimi
AU - Singh, Aditya
AU - Scala, Federico
AU - Chen, Haiying
AU - James, T. F.
AU - Alshammari, Musaad
AU - Panova-Elektronova, Neli I.
AU - White, Mark Andrew
AU - Zhou, Jia
AU - Laezza, Fernanda
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/5/16
Y1 - 2018/5/16
N2 - 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 + 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.
AB - 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 + 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.
KW - CNS drug discovery
KW - Fibroblast growth factor 14 (FGF14)
KW - minimal functional domains
KW - neurochemical probes
KW - peptidomimetics
KW - protein:protein interaction (PPI)
KW - voltage-gated sodium channels (Nav1.6)
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U2 - 10.1021/acschemneuro.7b00399
DO - 10.1021/acschemneuro.7b00399
M3 - Article
C2 - 29359916
AN - SCOPUS:85045217210
SN - 1948-7193
VL - 9
SP - 976
EP - 987
JO - ACS chemical neuroscience
JF - ACS chemical neuroscience
IS - 5
ER -