Identification of peptidomimetics as novel chemical probes modulating fibroblast growth factor 14 (FGF14) and voltage-gated sodium channel 1.6 (Nav1.6) protein-protein interactions

Q4 · MEDICINE

Article

Author: Wang, Pingyuan ; Singh, Aditya K ; Ali, Syed R ; Laezza, Fernanda ; Scaduto, Pietro ; Chen, Haiying ; Zhou, Jia ; Liu, Zhiqing ; Folorunso, Oluwarotimi ; Wadsworth, Paul

The voltage-gated sodium (Nav) channel is the molecular determinant of action potential in neurons. Protein-protein interactions (PPI) between the intracellular Nav1.6 C-tail and its regulatory protein fibroblast growth factor 14 (FGF14) provide an ideal and largely untapped opportunity for development of neurochemical probes. Based on a previously identified peptide FLPK, mapped to the FGF14:FGF14 PPI interface, we have designed and synthesized a series of peptidomimetics with the intent of increasing clogP values and improving cell permeability relative to the parental lead peptide. In-cell screening using the split-luciferase complementation (LCA) assay identified ZL0177 (13) as the most potent inhibitor of the FGF14:Nav1.6 channel complex assembly with an apparent IC₅₀ of 11 μM. Whole-cell patch-clamp recordings demonstrated that ZL0177 significantly reduced Nav1.6-mediated transient current density and induced a depolarizing shift of the channel voltage-dependence of activation. Docking studies revealed strong interactions between ZL0177 and Nav1.6, mediated by hydrogen bonds, cation-π interactions and hydrophobic contacts. All together these results suggest that ZL0177 retains some key features of FGF14-dependent modulation of Nav1.6 currents. Overall, ZL0177 provides a chemical scaffold for developing Nav channel modulators as pharmacological probes with therapeutic potential of interest for a broad range of CNS and PNS disorders.

16 May 2018·ACS Chemical NeuroscienceQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Miroslav N. Nenov ; Fernanda Laezza ; T. F. James ; Federico Scala ; Zhiqing Liu ; Haiying Chen ; Jia Zhou ; Oluwarotimi Folorunso ; Syed R Ali ; Neli I. Panova-Elektronova ; Aditya Kumar Singh ; Musaad Alshammari ; Mark Andrew White

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Demyelinating Autoimmune Diseases, CNS	Preclinical	United States	University of Texas Medical Branch	01 Feb 2019
Nervous System Paraneoplastic Syndromes	Preclinical	United States	University of Texas Medical Branch	01 Feb 2019

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