The application of toxins and venoms to cardiovascular drug discovery
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, including those from spiders, snakes, cone snails, scorpions and octopi, contain components that target the transmission 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 components that have profound effects on the cardiovascular system [2]. These include bradykinin-potentiating peptides (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 identified. 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 approximately the same time, Chen et al. [4] showed that bioactive peptides, and their corresponding mRNAs, could be characterized from extremely small quantities of Heloderma sp. lizard venom. This work has important ramifications given the limited supply of venom from these, often endangered or protected, animals.
Section snippets
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
Natriuretic peptides
The pharmacology of ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide; B-type natriuretic peptide) and CNP (C-type natriuretic peptide) has been well characterized. Their role in the diagnosis and therapy of cardiovascular disorders has been previously reviewed [9]. Natriuretic peptides are being identified in, and isolated from, an increasing number of animal venoms. These studies have been led by the early work of Schweitz et al. [10] who isolated Dendroaspis natriuretic
Incretin mimetics
The pharmacological control of hyperglycaemia, associated with Type II diabetes mellitus, has been largely based on the use of sulphonylurea compounds, metformin and, more recently, glitazones. However, the recent introduction of Exenatide as an adjunct therapy has provided a new focus for drug treatment [14]. Exenatide is an incretin mimetic based on exendin-4 that was isolated from the venom of the Gila monster (Heloderma suspectum) [15]. Exendin-4 is a 39 amino acid peptide, with structural
Sarafotoxins
The sarafotoxins are highly potent vasoconstrictor peptides with close structural homology to the endothelin family [20]. Sarafotoxins are 21 amino acid peptides, which were first isolated from the venom of Atractaspis engaddensis [21]. They have subsequently been identified in other Atractaspis spp. venoms (i.e. A. bibroni and A. microlepidota microlepidota) including a number of elongated peptides consisting of 24 amino acids [20]. The tertiary structure of the sarafotoxins, which is
Anti-arrhythmic toxins
The safe treatment of arrhythmias continues to be problematic because of the many side effects associated with currently available anti-arrhythmics. There has been limited but promising research into toxins that have anti-arrhythmic properties. Bode et al. [23] have shown that GsMtx-4, a 4 kDa toxin isolated from the venom of the tarantula Grammostola spatulata, blocks stretch activated ion channels (SACs) and is able to inhibit atrial fibrillation in rabbit hearts. Although the precise role of
Untapped potential
Many marine venoms possess profound cardiovascular activity with stonefish (Synanceia sp.) and box jellyfish being prime examples. The pharmacology of piscine venoms has been reviewed [26]; although, compared to venomous terrestrial animals, this is a relatively neglected area.
The venom of the Box jellyfish (Chironex fleckeri) is thought to be the most lethal venom in the world and it causes rapid cardiovascular collapse in vivo [27]. In addition, the venom of Chiropsella bronzie and two
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
Acknowledgements
WCH and GKI are funded by an NHMRC Project Grant (ID436606). GKI is also funded by an NHMRC Clinical Career Development Award (ID300785).
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