G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors
[en] 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. r-Da1a shown an affinity of 0.35 nM for the a1a-AR
while r-Da1b displayed affinities between 14 and 73 nM for the three a2-ARs. These two
venom peptides have sequences similar to those of muscarinic toxins and belong to the
three-finger-fold protein family. a1a-AR is the primary target for the treatment of prostate
hypertrophy. In vitro and in vivo tests demonstrated that r-Da1a reduced prostatic muscle
tone as efficiently as tamsulosin (an antagonist presently used), but with fewer cardiovascular
side effects. a2-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 r-Da1b antagonizes a2-ARs in
smooth muscles and increased heart rate and blood catecholamine concentrations. These
results highlight possible exploitation of r-Da1a and r-Da1b in important pathologies.
Disciplines :
Chemistry
Author, co-author :
Maïga, Arhamatoulaye; Commissariat à l'Energie Atomique (Saclay) - CEA > iBiTec-S > Service d’Ingénierie Moléculaire des Protéines (SIMOPRO)
Mourier, Gilles; Commissariat à l'Energie Atomique (Saclay) - CEA > iBiTec-S > Service d’Ingénierie Moléculaire des Protéines (SIMOPRO)
Quinton, Loïc ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie biologique
Rouget, Céline; Commissariat à l'Energie Atomique (Saclay) - CEA > iBiTec-S > Service d’Ingénierie Moléculaire des Protéines (SIMOPRO)
Gales, Céline
Denis, Colette
Lluel, Philippe
Palea, Stefano
Servent, Denis; Commissariat à l'Energie Atomique (Saclay) - CEA > iBiTec-S > Service d’Ingénierie Moléculaire des Protéines (SIMOPRO)
Gilles, Nicolas; Commissariat à l'Energie Atomique (Saclay) - CEA > iBiTec-S > Service d’Ingénierie Moléculaire des Protéines (SIMOPRO)
Language :
English
Title :
G protein-coupled receptors, an unexploited animal toxin targets: Exploration of green mamba venom for novel drug candidates active against adrenoceptors
Publication date :
March 2012
Journal title :
Toxicon
ISSN :
0041-0101
eISSN :
1879-3150
Publisher :
Pergamon Press - An Imprint of Elsevier Science, Oxford, United Kingdom
Acritopoulou-Fourcroy S., Marcais-Collado H. Involvement of alpha-adrenoceptors in myometrial responses in the pro-oestral rat. Br. J. Pharmacol. 1988, 93:185-191.
Bardou M., Loustalot C., Cortijo J., Simon B., Naline E., Dumas M., Esteve S., Croci T., Chalon P., Frydman R., Sagot P., Manara L., Morcillo E.J., Advenier C. Functional, biochemical and molecular biological evidence for a possible beta(3)-adrenoceptor in human near-term myometrium. Br. J. Pharmacol. 2000, 130:1960-1966.
Bradley K.N. Muscarinic toxins from the green mamba. Pharmacol. Ther. 2000, 85:87-109.
Bullock T.L., Andriole G.L. Emerging drug therapies for benign prostatic hyperplasia. Expert Opin. Emerg. Drugs 2006, 11:111-123.
Cheng Y., Prusoff W.H. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22:3099-3108.
Chien E.Y., Liu W., Zhao Q., Katritch V., Han G.W., Hanson M.A., Shi L., Newman A.H., Javitch J.A., Cherezov V., Stevens R.C. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 2010, 330:1091-1095.
Christopoulos A. Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat. Rev. Drug Discov. 2002, 1:198-210.
Christopoulos A., Kenakin T. G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 2002, 54:323-374.
Craig A.G., Norberg T., Griffin D., Hoeger C., Akhtar M., Schmidt K., Low W., Dykert J., Richelson E., Navarro V., Mazella J., Watkins M., Hillyard D., Imperial J., Cruz L.J., Olivera B.M. Contulakin-G, an O-glycosylated invertebrate neurotensin. J. Biol. Chem. 1999, 274:13752-13759.
Cruz L.J., de Santos V., Zafaralla G.C., Ramilo C.A., Zeikus R., Gray W.R., Olivera B.M. Invertebrate vasopressin/oxytocin homologs. Characterization of peptides from Conus geographus and Conus straitus venoms. J. Biol. Chem. 1987, 262:15821-15824.
Delaflotte S., Auguet M., Chabrier P.E. Pharmacological evidence that different alpha 1 adrenoceptor subtypes mediate contraction in rabbit prostate and hypogastric artery. Acta Physiol. Scand. 1996, 158:241-251.
Ducancel F. Endothelin-like peptides. Cell Mol. Life Sci. 2005, 62:2828-2839.
Harvey A.L., Kornisiuk E., Bradley K.N., Cervenansky C., Duran R., Adrover M., Sanchez G., Jerusalinsky D. Effects of muscarinic toxins MT1 and MT2 from green mamba on different muscarinic cholinoceptors. Neurochem. Res. 2002, 27:1543-1554.
Ibuki R., Haga N., Muramatsu S., Mizumoto A., Itoh Z. Long-term observations of uterine contractions in nonpregnant dogs. Biol. Reprod. 1997, 56:632-639.
Jaakola V.P., Ijzerman A.P. The crystallographic structure of the human adenosine A2A receptor in a high-affinity antagonist-bound state: implications for GPCR drug screening and design. Curr. Opin. Struct. Biol. 2010, 20:401-414.
Jacoby E., Bouhelal R., Gerspacher M., Seuwen K. The 7 TM G-protein-coupled receptor target family. Chem. Med. Chem. 2006, 1:761-782.
Jolkkonen M., Oras A., Toomela T., Karlsson E., Jarv J., Akerman K.E. Kinetic evidence for different mechanisms of interaction of black mamba toxins MT alpha and MT beta with muscarinic receptors. Toxicon 2001, 39:377-382.
Joubert F.J. The amino acid sequence of protein CM-3 from Dendroaspis polylepis polylepis (black mamba) venom. Int. J. Biochem. 1985, 17:695-699.
King G.F., Gentz M.C., Escoubas P., Nicholson G.M. A rational nomenclature for naming peptide toxins from spiders and other venomous animals. Toxicon 2008, 52:264-276.
Koivula K., Rondinelli S., Nasman J. The three-finger toxin MTalpha is a selective alpha(2B)-adrenoceptor antagonist. Toxicon 2010, 56:440-447.
Kojima Y., Sasaki S., Shinoura H., Hayashi Y., Tsujimoto G., Kohri K. Quantification of alpha1-adrenoceptor subtypes by real-time RT-PCR and correlation with age and prostate volume in benign prostatic hyperplasia patients. Prostate 2006, 66:761-767.
Kroeze W.K., Sheffler D.J., Roth B.L. G-protein-coupled receptors at a glance. J. Cell Sci. 2003, 116:4867-4869.
Lewis R.J., Garcia M.L. Therapeutic potential of venom peptides. Nat. Rev. Drug Discov. 2003, 2:790-802.
Ménez A., Gillet D., Grishin E. Toxins: threats and Benefits. Recent Research Developments in Toxins from Bacteria and Other Organisms 2006, 1-33. Research Signpost, Kerala. D. Gillet, L. Johannes (Eds.).
Menez A. Functional architectures of animal toxins: a clue to drug design?. Toxicon 1998, 36:1557-1572.
Michel M., Insel P. Adrenergic receptor in clinical medecine. The Adrenergic Receptors 2006, vol. 1:129-150. Humana Press, Totowa. P. DM (Ed.).
Michel M.C., Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br. J. Pharmacol. 2006, 147(Suppl. 2):S88-S119.
Nielsen D.B., Dykert J., Rivier J.E., McIntosh J.M. Isolation of Lys-conopressin-G from the venom of the worm-hunting snail, Conus imperialis. Toxicon 1994, 32:845-848.
O'Brien D.P., Senagore A., Merlino J., Brady K., Delaney C. Predictors and outcome of readmission after laparoscopic intestinal surgery. World J. Surg. 2007, 31:2430-2435.
Olivera B.M., Cruz L.J., de Santos V., LeCheminant G.W., Griffin D., Zeikus R., McIntosh J.M., Galyean R., Varga J., Gray W.R., et al. Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry 1987, 26:2086-2090.
Overington J.P., Al-Lazikani B., Hopkins A.L. How many drug targets are there?. Nat. Rev. Drug Discov. 2006, 5:993-996.
Quinton L., Girard E., Maiga A., Rekik M., Lluel P., Masuyer G., Larregola M., Marquer C., Ciolek J., Magnin T., Wagner R., Molgo J., Thai R., Fruchart-Gaillard C., Mourier G., Chamot-Rooke J., Menez A., Palea S., Servent D., Gilles N. Isolation and pharmacological characterization of AdTx1, a natural peptide displaying specific insurmountable antagonism of the alpha1A-adrenoceptor. Br. J. Pharmacol. 2010, 159:316-325.
Rajagopalan N., Pung Y.F., Zhu Y.Z., Wong P.T., Kumar P.P., Kini R.M. Beta-cardiotoxin: a new three-finger toxin from Ophiophagus hannah (king cobra) venom with beta-blocker activity. Faseb J. 2007, 21:3685-3695.
Rouget C., Quinton L., Maiga A., Gales C., Masuyer G., Malosse C., Chamot-Rooke J., Thai R., Mourier G., De Pauw E., Gilles N., Servent D. Identification of a novel snake peptide toxin displaying high affinity and antagonist behaviour for the alpha(2)-adrenoceptors. Br. J. Pharmacol. 2010, 161:1361-1374.
Savola J.M., Hill M., Engstrom M., Merivuori H., Wurster S., McGuire S.G., Fox S.H., Crossman A.R., Brotchie J.M. Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Mov Disord. 2003, 18:872-883.
Schmidtko A., Lotsch J., Freynhagen R., Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet 2010, 375:1569-1577.
Selvam e.a. J. Med. Chem. 2010, in revision.
Servent D., Fruchart-Gaillard C. Muscarinic toxins: tools for the study of the pharmacological and functional properties of muscarinic receptors. J. Neurochem 2009, 109:1193-1202.
Sharpe I.A., Gehrmann J., Loughnan M.L., Thomas L., Adams D.A., Atkins A., Palant E., Craik D.J., Adams D.J., Alewood P.F., Lewis R.J. Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter. Nat. Neurosci. 2001, 4:902-907.
Sharpe I.A., Thomas L., Loughnan M., Motin L., Palant E., Croker D.E., Alewood D., Chen S., Graham R.M., Alewood P.F., Adams D.J., Lewis R.J. Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA. J. Biol. Chem. 2003, 278:34451-34457.
Terlau H., Olivera B.M. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol. Rev. 2004, 84:41-68.
Thompson M.D., Burnham W.M., Cole D.E. The G protein-coupled receptors: pharmacogenetics and disease. Crit. Rev. Clin. Lab. Sci. 2005, 42:311-392.
Vassilatis D.K., Hohmann J.G., Zeng H., Li F., Ranchalis J.E., Mortrud M.T., Brown A., Rodriguez S.S., Weller J.R., Wright A.C., Bergmann J.E., Gaitanaris G.A. The G protein-coupled receptor repertoires of human and mouse. Proc. Natl. Acad. Sci. U S A 2003, 100:4903-4908.
Verwaerde P., Tran M.A., Montastruc J.L., Senard J.M., Portolan G. Effects of yohimbine, an alpha 2-adrenoceptor antagonist, on experimental neurogenic orthostatic hypotension. Fundam. Clin. Pharmacol. 1997, 11:567-575.
Westfall T., Westfall D. Adrenergic agonists and antagonists in the 21st century. The Adrenergic Receptors 2006, vol. 1:237-295. Humana press, Totowa, NJ. P. DM (Ed.).
Wu B., Chien E.Y., Mol C.D., Fenalti G., Liu W., Katritch V., Abagyan R., Brooun A., Wells P., Bi F.C., Hamel D.J., Kuhn P., Handel T.M., Cherezov V., Stevens R.C. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 2010, 330:1066-1071.
