TY - JOUR
T1 - 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
AU - Liu, Zhiqing
AU - Wadsworth, Paul
AU - Singh, Aditya K.
AU - Chen, Haiying
AU - Wang, Pingyuan
AU - Folorunso, Oluwarotimi
AU - Scaduto, Pietro
AU - Ali, Syed R.
AU - Laezza, Fernanda
AU - Zhou, Jia
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) Grants R01 MH095995 (F.L.), R01 MH111107 (F.L. and J.Z.), P30 DA028821 (J.Z.), John Sealy Memorial Endowments Fund (F.L.), Jeane B. Kempner Postdoctoral Fellowship (O.F.), NIA T32 Fellowship Grant No. T32 AG051131 (P.A.W.), and Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia NIGMS Grant T32 GM089657 (S.R.A.).
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - Chemical probes
KW - Fibroblast growth factor
KW - Protein-protein interactions
KW - Split-luciferase complementation assay
KW - Voltage-gated sodium channels
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U2 - 10.1016/j.bmcl.2018.12.031
DO - 10.1016/j.bmcl.2018.12.031
M3 - Article
C2 - 30587448
AN - SCOPUS:85058807763
VL - 29
SP - 413
EP - 419
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 3
ER -