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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Liu, Zhiqing¹  Wadsworth, Paul¹  Singh, Aditya K.¹  Chen, Haiying¹  Wang, Pingyuan¹  Folorunso, Oluwarotimi¹  Scaduto, Pietro¹  Ali, Syed R.¹  Laezza, Fernanda¹  Zhou, Jia¹ 

[1] Univ Texas Med Branch, Dept Pharmacol & Toxicol, 301 Univ Blvd, Galveston, TX 77555 USA

关键词: Voltage-gated sodium channels;    Fibroblast growth factor;    Chemical probes;    Protein-protein interactions;    Split-luciferase complementation assay;   

DOI  :  10.1016/j.bmcl.2018.12.031

来源: Elsevier

【 摘 要 】

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 mu M. 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-7C 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.

【 授权许可】

Free