Synthesis, pharmacological and structural characterization of novel conopressins from Conus miliaris

Giribaldi, Julien, Ragnarsson, Lotten, Pujante, Tom, Enjalbal, Christine, Wilson, David, Daly, Norelle L., Lewis, Richard J., and Dutertre, Sebastien (2020) Synthesis, pharmacological and structural characterization of novel conopressins from Conus miliaris. Marine Drugs, 18 (3). 150.

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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 a�nity. 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.

Item ID: 63062
Item Type: Article (Research - C1)
ISSN: 1660-3397
Keywords: conopressin; vasopressin; venom; cone snail; conotoxin
Copyright Information: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (
Funders: French Government (FG), French National Research Agency (ANR), National Health and Medical Research Council (NHMRC), Australian Research Council (ARC)
Projects and Grants: FG Ministry of Higher Education, Research and Innovation (PhD scholarship to J.G.), ANR-16-CE34-0002, NHMRC Program Grant (APP1072113), ARC LIEF Grant
Date Deposited: 12 May 2020 04:19
FoR Codes: 31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310112 Structural biology (incl. macromolecular modelling) @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320506 Medical biochemistry - proteins and peptides (incl. medical proteomics) @ 50%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 100%
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