Spider-venom peptides as therapeutics

Abstract

Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms are dominated by disulfide-rich peptides that typically have high affinity and specificity for particular subtypes of ion channels and receptors. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides, making them a valuable resource for drug discovery. Here we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against a wide range of pathophysiological conditions including cardiovascular disorders, chronic pain, inflammation, and erectile dysfunction.

Keywords: cystine knot; drug discovery; drugs; peptide; spider venom; therapeutics.

Figure 1

(A) The inhibitor cystine knot (ICK) motif comprises an antiparallel β sheet stabilized by a cystine knot. β strands are shown in orange and the six cysteine residues that form the cystine knot are labeled 1–6. In spider toxins, the β sheet typically comprises only the two β strands housing cysteine residues 5 and 6, although a third N-terminal strand encompassing cysteine 2 is sometimes present. The two “outer” disulfide bonds are shown in green and the “inner” disulfide bridge is red. (B) The cystine knot of the 37-residue spider-venom peptide ω-hexatoxin-Hv1a [43].The cystine knot comprises a ring formed by two disulfides (green) and the intervening sections of polypeptide backbone (gray), with a third disulfide (red) piercing the ring to create a pseudo-knot. The hydrophobic core of the toxin consists primarily of the two central disulfide bridges connected to the β strands. Key functional residues in ICK toxins are often located in the β hairpin that projects from the central disulfide-rich core of the peptide.

Figure 2

Spider-venom peptides that are serving as therapeutic leads. A photo of the spider from which each toxin was isolated is shown, and the name and 3D structure of the toxin is indicated at the bottom of each panel. Disulfide bonds are shown as green tubes, while β strands and α helices are highlighted in orange and red, respectively. The structure of δ-CNTX-Pn2a has not yet been determined. Note that therapeutic leads have been isolated from both “modern” (araneomorph) and “primitive” (mygalomorph) spiders [3].