Synthesis, Pharmacological and Structural Characterization of Novel Conopressins from Conus miliaris.
Mar Drugs
; 18(3)2020 Mar 06.
Article
em En
| MEDLINE
| ID: mdl-32155768
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Conotoxinas
/
Caramujo Conus
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Mar Drugs
Assunto da revista:
BIOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
França