Structure-function relationship of new peptides activating human Nav1.1
Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide com...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223009642 |
| _version_ | 1797744038117376000 |
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| author | Ludivine Lopez Stephan De Waard Hervé Meudal Cécile Caumes Kuldip Khakh Steve Peigneur Barbara Oliveira-Mendes Sophia Lin Jolien De Waele Jérôme Montnach Sandrine Cestèle Agnès Tessier J.P. Johnson Massimo Mantegazza Jan Tytgat Charles Cohen Rémy Béroud Frank Bosmans Céline Landon Michel De Waard |
| author_facet | Ludivine Lopez Stephan De Waard Hervé Meudal Cécile Caumes Kuldip Khakh Steve Peigneur Barbara Oliveira-Mendes Sophia Lin Jolien De Waele Jérôme Montnach Sandrine Cestèle Agnès Tessier J.P. Johnson Massimo Mantegazza Jan Tytgat Charles Cohen Rémy Béroud Frank Bosmans Céline Landon Michel De Waard |
| author_sort | Ludivine Lopez |
| collection | DOAJ |
| description | Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target. |
| first_indexed | 2024-03-12T15:03:59Z |
| format | Article |
| id | doaj.art-00c037522f374110a6181eefd130b12d |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-12T15:03:59Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-00c037522f374110a6181eefd130b12d2023-08-13T04:52:52ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-09-01165115173Structure-function relationship of new peptides activating human Nav1.1Ludivine Lopez0Stephan De Waard1Hervé Meudal2Cécile Caumes3Kuldip Khakh4Steve Peigneur5Barbara Oliveira-Mendes6Sophia Lin7Jolien De Waele8Jérôme Montnach9Sandrine Cestèle10Agnès Tessier11J.P. Johnson12Massimo Mantegazza13Jan Tytgat14Charles Cohen15Rémy Béroud16Frank Bosmans17Céline Landon18Michel De Waard19Nantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, France; Smartox Biotechnology, Saint-Egrève, FranceNantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, France; LabEx ''Ion Channels, Science and Therapeutics'', Valbonne, FranceCenter for Molecular Biophysics, CNRS, rue Charles Sadron, CS 80054, Orléans 45071, FranceSmartox Biotechnology, Saint-Egrève, FranceXenon Pharmaceuticals, Burnaby, British Columbia, CanadaUniversity of Leuven, 3000 Leuven, BelgiumNantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, FranceXenon Pharmaceuticals, Burnaby, British Columbia, CanadaDepartment of Basic and Applied Medical Sciences, Ghent University, Ghent, BelgiumNantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, FranceUniversité Cote d'Azur, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis, FranceNantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, FranceXenon Pharmaceuticals, Burnaby, British Columbia, CanadaUniversité Cote d'Azur, CNRS UMR 7275, Institute of Molecular and Cellular Pharmacology, Valbonne-Sophia Antipolis, FranceUniversity of Leuven, 3000 Leuven, BelgiumXenon Pharmaceuticals, Burnaby, British Columbia, CanadaSmartox Biotechnology, Saint-Egrève, FranceDepartment of Basic and Applied Medical Sciences, Ghent University, Ghent, BelgiumCenter for Molecular Biophysics, CNRS, rue Charles Sadron, CS 80054, Orléans 45071, FranceNantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, France; Smartox Biotechnology, Saint-Egrève, France; LabEx ''Ion Channels, Science and Therapeutics'', Valbonne, France; Corresponding author at: Nantes Université, CNRS, INSERM, l’institut du thorax, F-44000 Nantes, France.Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.http://www.sciencedirect.com/science/article/pii/S0753332223009642Drug discoveryJzTx-34PharmacologyhNav1.1 channelBiophysicsHigh-throughput screening |
| spellingShingle | Ludivine Lopez Stephan De Waard Hervé Meudal Cécile Caumes Kuldip Khakh Steve Peigneur Barbara Oliveira-Mendes Sophia Lin Jolien De Waele Jérôme Montnach Sandrine Cestèle Agnès Tessier J.P. Johnson Massimo Mantegazza Jan Tytgat Charles Cohen Rémy Béroud Frank Bosmans Céline Landon Michel De Waard Structure-function relationship of new peptides activating human Nav1.1 Biomedicine & Pharmacotherapy Drug discovery JzTx-34 Pharmacology hNav1.1 channel Biophysics High-throughput screening |
| title | Structure-function relationship of new peptides activating human Nav1.1 |
| title_full | Structure-function relationship of new peptides activating human Nav1.1 |
| title_fullStr | Structure-function relationship of new peptides activating human Nav1.1 |
| title_full_unstemmed | Structure-function relationship of new peptides activating human Nav1.1 |
| title_short | Structure-function relationship of new peptides activating human Nav1.1 |
| title_sort | structure function relationship of new peptides activating human nav1 1 |
| topic | Drug discovery JzTx-34 Pharmacology hNav1.1 channel Biophysics High-throughput screening |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223009642 |
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