期刊
MOLECULES
卷 25, 期 15, 页码 -出版社
MDPI
DOI: 10.3390/molecules25153365
关键词
protein; protein interactions (PPIs); voltage-gated Na+(Nav) channels; fibroblast growth factor 14 (FGF14); peptidomimetics; molecular docking; neurotherapeutics
资金
- National Institute of Health (NIH) [R01 MH095995, R01 MH111107, R01 MH124351, S10 OD023576]
- UTMBTechnology Commercialization Program
- John D. Stobo, M.D. Distinguished Chair Endowment Fund
- John Sealy Memorial Endowment Fund
- NIA [T32 AG051131]
- Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation Pre-doctoral Fellowship in Pharmacology/Toxicology
- [P30 DA028821]
- NATIONAL INSTITUTE ON DRUG ABUSE [U18DA052504] Funding Source: NIH RePORTER
Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na+(Nav) channels leads to neural circuitry aberrations that have been implicated in numerous channelopathies. One example of this pathophysiology is mediated by dysfunction of the PPI between Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). Thus, peptides derived from FGF14 might exert modulatory actions on the FGF14:Nav1.6 complex that are functionally relevant. The tetrapeptide Glu-Tyr-Tyr-Val (EYYV) mimics surface residues of FGF14 at the beta 8-beta 9 loop, a structural region previously implicated in its binding to Nav1.6. Here, peptidomimetics derived from EYYV (6) were designed, synthesized, and pharmacologically evaluated to develop probes with improved potency. Addition of hydrophobic protective groups to6and truncation to a tripeptide (12) produced a potent inhibitor of FGF14:Nav1.6 complex assembly. Conversely, addition of hydrophobic protective groups to6followed by addition of anN-terminal benzoyl substituent (19) produced a potentiator of FGF14:Nav1.6 complex assembly. Subsequent functional evaluation using whole-cell patch-clamp electrophysiology confirmed their inverse activities, with12and19reducing and increasing Nav1.6-mediated transient current densities, respectively. Overall, we have identified a negative and positive allosteric modulator of Nav1.6, both of which could serve as scaffolds for the development of target-selective neurotherapeutics.
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