PUBLICATION
Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris
- Authors
- Giribaldi, J., Ragnarsson, L., Pujante, T., Enjalbal, C., Wilson, D., Daly, N.L., Lewis, R.J., Dutertre, S.
- ID
- ZDB-PUB-200403-26
- Date
- 2020
- Source
- Marine drugs 18(3): (Journal)
- Registered Authors
- Keywords
- cone snail, conopressin, conotoxin, vasopressin, venom
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Conotoxins/chemical synthesis
- Conotoxins/chemistry*
- Conotoxins/pharmacology*
- Conus Snail/chemistry*
- Disulfides/chemistry
- Disulfides/pharmacology
- Humans
- Molecular Conformation
- Mollusk Venoms/chemistry
- Neurophysins/antagonists & inhibitors
- Protein Precursors/antagonists & inhibitors
- Receptors, Oxytocin/drug effects
- Receptors, Vasopressin/drug effects
- Structure-Activity Relationship
- Transcriptome
- Vasopressins/antagonists & inhibitors
- Zebrafish
- PubMed
- 32155768 Full text @ Mar. Drugs
Citation
Giribaldi, J., Ragnarsson, L., Pujante, T., Enjalbal, C., Wilson, D., Daly, N.L., Lewis, R.J., Dutertre, S. (2020) Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris. Marine drugs. 18(3):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping