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ß-Cardiotoxin: a new three-finger toxin from Ophiophagus hannah (king cobra) venom with beta-blocker activity

Nandhakishore Rajagopalan^*, Yuh Fen Pung^*, Yi Zhun Zhu, Peter Tsun Hon Wong, Prakash P. Kumar^*,,1 and R. Manjunatha Kini^*,,1

^* Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore;

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;

Temasek Life Sciences Laboratory, National University of Singapore, Singapore; and

Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA

¹Correspondence: Protein Science Laboratory, Department of Biological Sciences, Faculty of Science, National University of Singapore, Science Dr. 4, Singapore 117543. E-mail: dbskinim{at}nus.edu.sg (R.M.K.); Plant Morphogenesis Laboratory, Department of Biological Sciences, Faculty of Science, National University of Singapore, Science Dr. 4, Singapore 117543. E-mail: dbskumar{at}nus.edu.sg (P.P.K.)

Snake venoms have provided a number of novel ligands with therapeutic potential. We have constructed a partial cDNA library from the mRNA of Ophiophagus hannah (king cobra) venom gland tissue and identified five new genes encoding proteins belonging to the three-finger toxin family of snake venom proteins. We have isolated and characterized one of these ß-sheet containing proteins with a mass of 7012.43 ± 0.91 Da from the venom. The protein was nonlethal up to a dose of 10 mg/kg when injected intraperitoneally into Swiss albino mice. However, it induces labored breathing and death at a dose of 100 mg/kg. It does not show any hemolytic or anticoagulant activity. It caused a dose-dependent decrease of heart rate in vivo (anesthetized Sprague-Dawley rats) and also ex vivo (Langendorff isolated rat heart). This is in contrast to classical cardiotoxins from snake venom that increase the heart rate in animals. Radioligand displacement studies showed that this protein targets ß-adrenergic receptors with a binding affinity (K_i) of 5.3 and 2.3 µM toward ß₁ and ß₂ subtypes, respectively, to bring about its effect, and hence, it was named as ß-cardiotoxin. This is the first report of a natural exogenous beta-blocker.—Rajagopalan, N., Pung, Y. F., Zhu, Y. Z., Wong, P. T. H., Kumar, P. P., Kini, R. M. ß-Cardiotoxin: a new three-finger toxin from Ophiophagus hannah (king cobra) venom with beta-blocker activity.

Key Words: heart rate • bradycardia • adrenergic receptors • GPCR ligands • beta-blocker peptide