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Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic.

ACS Chem Neurosci. 2018 May 16;9(5):976-987. doi:10.1021/acschemneuro.7b00399. Epub 2018 Feb 06
Syed R Ali , Zhiqing Liu , Miroslav N Nenov , Oluwarotimi Folorunso , Aditya Singh , Federico Scala , Haiying Chen , T F James , Musaad Alshammari 1 , Neli I Panova-Elektronova , Mark Andrew White , Jia Zhou , Fernanda Laezza
Syed R Ali , Zhiqing Liu , Miroslav N Nenov , Oluwarotimi Folorunso , Aditya Singh , Federico Scala , Haiying Chen , T F James , Musaad Alshammari 1 , Neli I Panova-Elektronova , Mark Andrew White , Jia Zhou , Fernanda Laezza
+ et al

[No authors listed]

Author information
  • 1 King Saud University Graduate Studies Abroad Program , King Saud University , Riyadh , Saudi Arabia.

摘要


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.

KEYWORDS: CNS drug discovery, Fibroblast growth factor 14 (FGF14), minimal functional domains, neurochemical probes, peptidomimetics, protein:protein interaction (PPI), voltage-gated sodium channels (Nav1.6)