title: G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors.
abstract: At a time when pharmaceutical companies are having trouble finding new low MW drugs and when biologics are becoming more common, animal venoms could constitute an underexploited source of novel drug candidates. We looked for identifying novel animal toxins active against G protein-coupled receptors (GPCR), the most frequently exploited class of treatment targets, with the aim to develop novel research tools and drug candidates. Screening of green mamba (Dendroaspis angusticeps) venom against adrenoceptors identified two novel venom peptides. ρ-Da1a shown an affinity of 0.35 nM for the α1a-AR while ρ-Da1b displayed affinities between 14 and 73 nM for the three α2-ARs. These two venom peptides have sequences similar to those of muscarinic toxins and belong to the three-finger-fold protein family. α1a-AR is the primary target for the treatment of prostate hypertrophy. In vitro and in vivo tests demonstrated that ρ-Da1a reduced prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects. α2-ARs are the prototype of GPCRs not currently used as treatment targets due to a lack of specific ligands. Blockage of these receptors increases intestinal motility, which may be compromised by abdominal surgery and reduces orthosteric hypotension. In vitro and in vivo tests demonstrated that ρ-Da1b antagonizes α2-ARs in smooth muscles and increased heart rate and blood catecholamine concentrations. These results highlight possible exploitation of ρ-Da1a and ρ-Da1b in important pathologies.
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Arhamatoulaye
authors.initials: A
authors.lastname: Maïga
authors.forename: Gilles
authors.initials: G
authors.lastname: Mourier
authors.forename: Loïc
authors.initials: L
authors.lastname: Quinton
authors.forename: Céline
authors.initials: C
authors.lastname: Rouget
authors.forename: Céline
authors.initials: C
authors.lastname: Gales
authors.forename: Colette
authors.initials: C
authors.lastname: Denis
authors.forename: Philippe
authors.initials: P
authors.lastname: Lluel
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Sénard
authors.forename: Stefano
authors.initials: S
authors.lastname: Palea
authors.forename: Denis
authors.initials: D
authors.lastname: Servent
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gilles
mesh_terms: D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D055808:Drug Discovery; D004546:Elapid Venoms / Q000494:pharmacology*; D017815:Elapidae; D007022:Hypotension / Q000188:drug therapy; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D011184:Postoperative Period; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D016415:Sequence Alignment
chemical_list: D018674:Adrenergic Antagonists; D004546:Elapid Venoms; D008024:Ligands; D011941:Receptors, Adrenergic; D043562:Receptors, G-Protein-Coupled