@article{166498c6dd214337a64de00ac3247434,
title = "Design, Synthesis, and Pharmacological Evaluation of Analogues Derived from the PLEV Tetrapeptide as Protein-Protein Interaction Modulators of Voltage-Gated Sodium Channel 1.6",
abstract = "The voltage-gated Na+ (Nav) channel is the molecular determinant of excitability. Disruption of protein-protein interactions (PPIs) between Nav1.6 and fibroblast growth factor 14 (FGF14) leads to impaired excitability of neurons in clinically relevant brain areas associated with channelopathies. Here, we designed, synthesized, and pharmacologically characterized new peptidomimetics based on a PLEV tetrapeptide scaffold derived from the FGF14:Nav1.6 PPI interface. Addition of an N-terminal 1-adamantanecarbonyl pharmacophore significantly improved peptidomimetic inhibitory potency. Surface plasmon resonance studies revealed that while this moiety was sufficient to confer binding to FGF14, altering the C-terminal moiety from methoxy (21a) to πbond-containing (23a and 23b) or cycloalkane substituents (23e) abrogated the binding to Nav1.6. Whole-cell patch-clamp electrophysiology subsequently revealed that 21a had functionally relevant interactions with both the C-terminal tail of Nav1.6 and FGF14. Collectively, these findings support that 21a (PW0564) may serve as a promising lead to develop target-selective neurotherapeutics by modulating protein-channel interactions.",
author = "Pingyuan Wang and Wadsworth, {Paul A.} and Dvorak, {Nolan M.} and Singh, {Aditya K.} and Haiying Chen and Zhiqing Liu and Richard Zhou and Holthauzen, {Luis Marcelo F.} and Jia Zhou and Fernanda Laezza",
note = "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 D. Stobo, M.D., Distinguished Chair Endowment Fund (J.Z.), John Sealy Memorial Endowment Fund (F.L.), UTMB Technology Commercialization Program (F.L. and J.Z.), NIA T32 Fellowship Grant No. T32 AG051131 (P.A.W.), the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Pre-doctoral Fellowship in Pharmacology/Toxicology (P.A.W.), and the Houston Area Molecular Biophysics Program Grant No. T32 GM008280 (N.M.D). We would also like to thank Drs. Lawrence C. Sowers and Jason Herring at the Department of Pharmacology as well as Dr. Tianzhi Wang at the NMR core facility of UTMB for the NMR spectroscopy assistance, and Dr. William Russell at UTMB mass spectrometry core with funding support from UT system proteomics network for the HRMS analysis. Publisher Copyright: {\textcopyright} ",
year = "2020",
month = oct,
day = "22",
doi = "10.1021/acs.jmedchem.0c00531",
language = "English (US)",
volume = "63",
pages = "11522--11547",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "20",
}