Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics
Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na<sup>+</sup> (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 P...
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MDPI AG
2020-07-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/15/3365 |
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| author | Nolan M. Dvorak Paul A. Wadsworth Pingyuan Wang Haiying Chen Jia Zhou Fernanda Laezza |
| author_facet | Nolan M. Dvorak Paul A. Wadsworth Pingyuan Wang Haiying Chen Jia Zhou Fernanda Laezza |
| author_sort | Nolan M. Dvorak |
| collection | DOAJ |
| description | Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na<sup>+</sup> (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 β8–β9 loop, a structural region previously implicated in its binding to Nav1.6. Here, peptidomimetics derived from EYYV (<b>6</b>) were designed, synthesized, and pharmacologically evaluated to develop probes with improved potency. Addition of hydrophobic protective groups to <b>6</b> and truncation to a tripeptide (<b>12</b>) produced a potent inhibitor of FGF14:Nav1.6 complex assembly. Conversely, addition of hydrophobic protective groups to <b>6</b> followed by addition of an <i>N</i>-terminal benzoyl substituent (<b>19</b>) produced a potentiator of FGF14:Nav1.6 complex assembly. Subsequent functional evaluation using whole-cell patch-clamp electrophysiology confirmed their inverse activities, with <b>12</b> and <b>19</b> reducing 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. |
| first_indexed | 2024-03-10T18:13:44Z |
| format | Article |
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| language | English |
| last_indexed | 2024-03-10T18:13:44Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-251a6d6ae02741e7978c8c9fabb7640d2023-11-20T07:52:26ZengMDPI AGMolecules1420-30492020-07-012515336510.3390/molecules25153365Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed PeptidomimeticsNolan M. Dvorak0Paul A. Wadsworth1Pingyuan Wang2Haiying Chen3Jia Zhou4Fernanda Laezza5Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 75901, USADepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 75901, USADepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 75901, USADepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 75901, USADepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 75901, USADepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 75901, USADisruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na<sup>+</sup> (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 β8–β9 loop, a structural region previously implicated in its binding to Nav1.6. Here, peptidomimetics derived from EYYV (<b>6</b>) were designed, synthesized, and pharmacologically evaluated to develop probes with improved potency. Addition of hydrophobic protective groups to <b>6</b> and truncation to a tripeptide (<b>12</b>) produced a potent inhibitor of FGF14:Nav1.6 complex assembly. Conversely, addition of hydrophobic protective groups to <b>6</b> followed by addition of an <i>N</i>-terminal benzoyl substituent (<b>19</b>) produced a potentiator of FGF14:Nav1.6 complex assembly. Subsequent functional evaluation using whole-cell patch-clamp electrophysiology confirmed their inverse activities, with <b>12</b> and <b>19</b> reducing 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.https://www.mdpi.com/1420-3049/25/15/3365protein:protein interactions (PPIs)voltage-gated Na<sup>+</sup> (Nav) channelsfibroblast growth factor 14 (FGF14)peptidomimeticsmolecular dockingneurotherapeutics |
| spellingShingle | Nolan M. Dvorak Paul A. Wadsworth Pingyuan Wang Haiying Chen Jia Zhou Fernanda Laezza Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics Molecules protein:protein interactions (PPIs) voltage-gated Na<sup>+</sup> (Nav) channels fibroblast growth factor 14 (FGF14) peptidomimetics molecular docking neurotherapeutics |
| title | Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics |
| title_full | Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics |
| title_fullStr | Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics |
| title_full_unstemmed | Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics |
| title_short | Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics |
| title_sort | bidirectional modulation of the voltage gated sodium nav1 6 channel by rationally designed peptidomimetics |
| topic | protein:protein interactions (PPIs) voltage-gated Na<sup>+</sup> (Nav) channels fibroblast growth factor 14 (FGF14) peptidomimetics molecular docking neurotherapeutics |
| url | https://www.mdpi.com/1420-3049/25/15/3365 |
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