Available online at www.sciencedirect.com The application of toxins and venoms to cardiovascular drug discovery Wayne C Hodgson 1 and Geoffrey K Isbister 1,2,3 Animal venoms contain a variety of highly selective and potent toxins, which have evolved over thousands/millions of years, which target vital physiological processes. As such, they have proven to be an excellent source of lead compounds for the development of therapeutic agents. In particular, a number of these venom components (e.g. bradykinin-potentiating peptides, sarafotoxins, natriuretic peptides) have profound effects on the cardiovascular system. This review article examines recent progress in the search for lead compounds or novel scaffolds for cardiovascular drug development from animal venoms. Addresses 1 Monash Venom Group, Department of Pharmacology, Monash University, Victoria, Australia 2 Tropical Toxinology Unit, Menzies School of Health Research, Charles Darwin University, Darwin, Australia 3 Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle Hospital, Newcastle, New South Wales, Australia Corresponding authors: Hodgson, Wayne C (wayne.hodgson@med.monash.edu.au) and Isbister, Geoffrey K (geoff.isbister@gmail.com) Current Opinion in Pharmacology 2009, 9:173–176 This review comes from a themed issue on Cardiovascular and renal Edited by Michael Curtis Available online 26th December 2008 1471-4892/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2008.11.007 Introduction The search for lead compounds for the development of new therapeutic agents has long included a focus on animal venoms. This is primarily because venomous animals have evolved complex mixtures of toxins that target vital physiological processes in their prey and, inadvertently, often in humans. Most animal toxins are highly selective and potent, qualities that often make them ideal lead compounds. Many animal venoms, in- cluding those from spiders, snakes, cone snails, scorpions and octopi, contain components that target the trans- mission of nerve impulses (i.e. neurotoxins) because this results in rapid immobilization or death of the animal’s prey [1]. However, there are also many venom com- ponents that have profound effects on the cardiovascular system [2]. These include bradykinin-potentiating pep- tides (BPPs), natriuretic peptides and sarafotoxins. Some snake toxins affect the clotting cascade resulting in severe coagulopathic disturbances but will not be considered in this review. The former cardiovascular toxins will be the focus of this review article. While snake venoms have been at the forefront of much toxinology research, a study by Fry et al.[3  ] has shown that the ‘pool’ of understudied/ unstudied venoms is much larger than previously ident- ified. This work showed that two additional lizard lineages (i.e. Monitor Lizards and Iguania) possessed venom apparatus and demonstrated a single early origin of the venom system in lizards and snakes. At approxi- mately the same time, Chen et al.[4] showed that bioac- tive peptides, and their corresponding mRNAs, could be characterized from extremely small quantities of Helo- derma sp. lizard venom. This work has important ramifi- cations given the limited supply of venom from these, often endangered or protected, animals. Bradykinin-potentiating peptides High profile examples of venoms/toxins used in the development of drugs for cardiovascular disease are plentiful, including the development of the angiotensin converting enzyme (ACE) inhibitors. The classic work of Ferreira on Bothrops jararaca (Brazilian pit viper) venom discovered the bradykinin-potentiating peptides (BPP) [5] that then led to the development of the ACE inhibitors. Since this early work, a vast number of studies have focused on the identification and characterization of BPP’s from a variety of natural sources with a recent focus on structure–function relationships [6]. These venom components inhibit the breakdown of the endogenous vasodilator bradykinin while also inhibiting the synthesis of the endogenous vasoconstrictor angio- tensin II, leading to a reduction in systemic blood pressure. Interestingly, Conceic ¸a ˜o and co-workers [7] have recently isolated a BPP, Phypo Xa (10 amino acid residues; 1215 Da), from the skin of Phyllomedusa hypo- chondrialis (Brazilian tigerleg monkey tree frog). While Verano-Braga et al.[8  ] have recently discovered a group of BPPs in Tityus serrulatus (yellow scorpion) venom. Four peptides (i.e. T. serrulatus Hypotensins: TsHpt-I, TsHpt-II, TsHpt-III and TsHpt IV) were identified containing 24–25 amino acid residues with molecular weights ranging from 2600 to 2800 Da. They display bradykinin-potentiating activity in the absence of ACE inhibition and appear to produce their anti-hypertensive activity via nitric oxide (NO)-dependent mechanisms. The pharmacological activity of these peptides appears to be located towards the C-terminal as a truncated www.sciencedirect.com Current Opinion in Pharmacology 2009, 9:173–176