G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors

摘要

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. rho-Da1a shown an affinity of 0.35 nM for the alpha 1a-AR while rho-Da1b displayed affinities between 14 and 73 nM for the three alpha 2-ARs. These two venom peptides have sequences similar to those of muscarinic toxins and belong to the three-finger-fold protein family. alpha 1a-AR is the primary target for the treatment of prostate hypertrophy. In vitro and in vivo tests demonstrated that rho-Da1a reduced prostatic muscle tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular side effects. alpha 2-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 rho-Da1b antagonizes alpha 2-ARs in smooth muscles and increased heart rate and blood catecholamine concentrations. These results highlight possible exploitation of rho-Da1a and rho-Da1b in important pathologies. (C) 2011 Elsevier Ltd. All rights reserved.