Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i>
Cone snails produce a fast-acting and often paralyzing venom, largely dominated by disulfide-rich conotoxins targeting ion channels. Although disulfide-poor conopeptides are usually minor components of cone snail venoms, their ability to target key membrane receptors such as GPCRs make them highly v...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-03-01
|
| Series: | Marine Drugs |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1660-3397/18/3/150 |
| _version_ | 1797999161509937152 |
|---|---|
| author | Julien Giribaldi Lotten Ragnarsson Tom Pujante Christine Enjalbal David Wilson Norelle L. Daly Richard J. Lewis Sebastien Dutertre |
| author_facet | Julien Giribaldi Lotten Ragnarsson Tom Pujante Christine Enjalbal David Wilson Norelle L. Daly Richard J. Lewis Sebastien Dutertre |
| author_sort | Julien Giribaldi |
| collection | DOAJ |
| description | Cone snails produce a fast-acting and often paralyzing venom, largely dominated by disulfide-rich conotoxins targeting ion channels. Although disulfide-poor conopeptides are usually minor components of cone snail venoms, their ability to target key membrane receptors such as GPCRs make them highly valuable as drug lead compounds. From the venom gland transcriptome of <i>Conus miliaris</i>, we report here on the discovery and characterization of two conopressins, which are nonapeptide ligands of the vasopressin/oxytocin receptor family. These novel sequence variants show unusual features, including a charge inversion at the critical position 8, with an aspartate instead of a highly conserved lysine or arginine residue. Both the amidated and acid C-terminal analogues were synthesized, followed by pharmacological characterization on human and zebrafish receptors and structural investigation by NMR. Whereas conopressin-M1 showed weak and only partial agonist activity at hV1bR (amidated form only) and ZFV1a1R (both amidated and acid form), both conopressin-M2 analogues acted as full agonists at the ZFV2 receptor with low micromolar affinity. Together with the NMR structures of amidated conopressins-M1, -M2 and -G, this study provides novel structure-activity relationship information that may help in the design of more selective ligands. |
| first_indexed | 2024-04-11T11:00:13Z |
| format | Article |
| id | doaj.art-e60e84aa1dd84920924f1408896ca617 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-11T11:00:13Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-e60e84aa1dd84920924f1408896ca6172022-12-22T04:28:39ZengMDPI AGMarine Drugs1660-33972020-03-0118315010.3390/md18030150md18030150Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i>Julien Giribaldi0Lotten Ragnarsson1Tom Pujante2Christine Enjalbal3David Wilson4Norelle L. Daly5Richard J. Lewis6Sebastien Dutertre7Institut des Biomolécules Max Mousseron, UMR 5247, Université de Montpellier-CNRS, 34095 Montpellier, FranceInstitute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, AustraliaInstitut des Biomolécules Max Mousseron, UMR 5247, Université de Montpellier-CNRS, 34095 Montpellier, FranceInstitut des Biomolécules Max Mousseron, UMR 5247, Université de Montpellier-CNRS, 34095 Montpellier, FranceCentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, AustraliaCentre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, AustraliaInstitute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, AustraliaInstitut des Biomolécules Max Mousseron, UMR 5247, Université de Montpellier-CNRS, 34095 Montpellier, FranceCone snails produce a fast-acting and often paralyzing venom, largely dominated by disulfide-rich conotoxins targeting ion channels. Although disulfide-poor conopeptides are usually minor components of cone snail venoms, their ability to target key membrane receptors such as GPCRs make them highly valuable as drug lead compounds. From the venom gland transcriptome of <i>Conus miliaris</i>, we report here on the discovery and characterization of two conopressins, which are nonapeptide ligands of the vasopressin/oxytocin receptor family. These novel sequence variants show unusual features, including a charge inversion at the critical position 8, with an aspartate instead of a highly conserved lysine or arginine residue. Both the amidated and acid C-terminal analogues were synthesized, followed by pharmacological characterization on human and zebrafish receptors and structural investigation by NMR. Whereas conopressin-M1 showed weak and only partial agonist activity at hV1bR (amidated form only) and ZFV1a1R (both amidated and acid form), both conopressin-M2 analogues acted as full agonists at the ZFV2 receptor with low micromolar affinity. Together with the NMR structures of amidated conopressins-M1, -M2 and -G, this study provides novel structure-activity relationship information that may help in the design of more selective ligands.https://www.mdpi.com/1660-3397/18/3/150conopressinvasopressinvenomcone snailconotoxin |
| spellingShingle | Julien Giribaldi Lotten Ragnarsson Tom Pujante Christine Enjalbal David Wilson Norelle L. Daly Richard J. Lewis Sebastien Dutertre Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i> Marine Drugs conopressin vasopressin venom cone snail conotoxin |
| title | Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i> |
| title_full | Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i> |
| title_fullStr | Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i> |
| title_full_unstemmed | Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i> |
| title_short | Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from <i>Conus miliaris</i> |
| title_sort | synthesis pharmacological and structural characterization of novel conopressins from i conus miliaris i |
| topic | conopressin vasopressin venom cone snail conotoxin |
| url | https://www.mdpi.com/1660-3397/18/3/150 |
| work_keys_str_mv | AT juliengiribaldi synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT lottenragnarsson synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT tompujante synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT christineenjalbal synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT davidwilson synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT norelleldaly synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT richardjlewis synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi AT sebastiendutertre synthesispharmacologicalandstructuralcharacterizationofnovelconopressinsfromiconusmiliarisi |