Animal toxins - Nature's evolutionary-refined toolkit for basic research and drug discovery

Abstract

Venomous animals have evolved toxins that interfere with specific components of their victim's core physiological systems, thereby causing biological dysfunction that aids in prey capture, defense against predators, or other roles such as intraspecific competition. Many animal lineages evolved venom systems independently, highlighting the success of this strategy. Over the course of evolution, toxins with exceptional specificity and high potency for their intended molecular targets have prevailed, making venoms an invaluable and almost inexhaustible source of bioactive molecules, some of which have found use as pharmacological tools, human therapeutics, and bioinsecticides. Current biomedically-focused research on venoms is directed towards their use in delineating the physiological role of toxin molecular targets such as ion channels and receptors, studying or treating human diseases, targeting vectors of human diseases, and treating microbial and parasitic infections. We provide examples of each of these areas of venom research, highlighting the potential that venom molecules hold for basic research and drug development.

Keywords: Drug discovery; Insecticides; Pharmacological tools; Therapeutics; Venom; Venom peptides.

Graphical abstract

Fig. 1

Fields of application in basic research and human health to which venom compounds have been applied. Venom compounds have the potential to be used as pharmacological tools, therapeutics, insecticides, or for targeting vectors of human disease or disease-inducing organisms.

Fig. 2

The diversity in molecular structures of venom-derived toxins and their targets. The Protein Data Bank accession codes are indicated. (A) Snake toxin complexes: α-bungarotoxin bound to the α1 extracellular domain of the nicotinic acetylcholine receptor (2qc1) (nAChR) ; botrocetin bound to von Willebrand Factor (vWF) and platelet glycoprotein Ib (GPIb) (1u0n) ; cobra venom factor (CVF) bound to complement factor B (3hrz) ; captopril bound to angiotensin converting enzyme (ACE) (1uzf) ; triflin bound to small serum protein 2 (SSP2) (6imf) ; MitTx-α and –β bound to acid sensing ion channel 1 (ASIC1) (4ntw) . (B) Cone snail toxin complexes: α-conotoxin ImI bound to acetylcholine binding protein (AChBP) (2byp) ; μ-conotoxin KIIIA bound to voltage-gated sodium channel (Na_V)1.2/auxiliary β2 subunit (6j8e) . (C) Spider toxin complexes: PcTx1 bound to ASIC1 (4fz0) ; Dc1a and tetrodotoxin (TTX) bound to Na_VPaS (6a95) ; DkTx and resiniferatoxin (RTX) bound to transient receptor potential cation channel subfamily V member 1 (TRPV1) (5irx) ; ProTx-II bound to Na_V1.7 voltage sensor domain II/Na_VAB chimera (6n4i) . (D) Gila monster toxin exendin-4 to bound glucagon-like peptide 1 receptor (GLP-1R) (3c5t) . (E) Scorpion toxin complexes: charybdotoxin (CTX) bound to voltage-gated potassium channel (K_V) 1.2–2.1 paddle chimera (4jta) ; α-mammal toxin AaH2 bound to human-cockroach hybrid Na_V channel (6nt4) . Structures are shown as a cartoon representation and from two angles (90° rotation). Toxin components are shown in purple and with a transparent surface representation where possible (note: TTX and RTX are shown as red sticks). Where applicable for the target structure, protein subunits or domains are colored differently. Structures are not to scale.

Fig. 3

Toxins providing insight into the pathophysiological role of specific ion channels in sensory neurons. Subtype-selective Na_V channel activators, including δ-TRTX-Hm1a and the scorpion toxins Cn2 and OD1, have highlighted modality-specific nociceptive roles for Na_V1.1, Na_V1.6 and Na_V1.7, respectively, in sensory neurons. Activation of Na_V1.7 by the scorpion toxin OD1 leads to spontaneous action potential firing in myelinated A-fibres and unmyelinated C-fibres, while activation of Na_V1.1 leads to symptoms of mechanical allodynia and increased mechanical sensitivity. Cn2, a selective Na_V1.6 activator, elicits pain behaviour and mechanical allodynia after local administration consistent with effects on myelinated A-fibres. Similarly, cold pain induced by ciguatoxin is elicited by selective activation of unmyelinated peripheral sensory neurons expressing the cold-sensitive TRPA1 and Na_V1.8 channels, while α-dendrotoxin revealed a crucial role for K_V1.1 in setting the activation threshold of cold-sensitive C-fibre neurons.