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Structure-Function Elucidation of a New α-Conotoxin, MilIA, from Conus milneedwardsi
Open AccessArticle

Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris

1
Institut des Biomolécules Max Mousseron, UMR 5247, Université de Montpellier-CNRS, 34095 Montpellier, France
2
Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia
3
Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD 4878, Australia
*
Author to whom correspondence should be addressed.
Mar. Drugs 2020, 18(3), 150; https://doi.org/10.3390/md18030150
Received: 13 February 2020 / Revised: 28 February 2020 / Accepted: 2 March 2020 / Published: 6 March 2020
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 Conus miliaris, 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. View Full-Text
Keywords: conopressin; vasopressin; venom; cone snail; conotoxin conopressin; vasopressin; venom; cone snail; conotoxin
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Giribaldi, J.; Ragnarsson, L.; Pujante, T.; Enjalbal, C.; Wilson, D.; Daly, N.L.; Lewis, R.J.; Dutertre, S. Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris. Mar. Drugs 2020, 18, 150.

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