Venom: the sharp end of pain therapeutics

Abstract

Adequate pain control is still a significant challenge and largely unmet medical need in the 21st century. With many small molecules failing to reach required levels of potency and selectivity, drug discovery is once again turning to nature to replenish pain therapeutic pipelines. Venomous animals are frequently stereotyped as inflictors of pain and distress and have historically been vilified by mankind. Yet, ironically, the very venoms that cause pain when directly injected by the host animal may actually turn out to contain the next generation of analgesics when injected by the clinician. The last 12 months have seen dramatic discoveries of analgesic tools within venoms. Spiders, snakes and even centipedes are yielding peptides with immense therapeutic potential. Significant advances are also taking place in delivery methods that can improve bioavailability and pharmacokinetics of these exciting natural resources. Turning proteinaceous venom into pharmaceutical liquid gold is the goal of venomics and the focus of this article.

Keywords: Nociception; analgesic; ion channel; pain; toxin; venom.

Figure 1.

Schematic binding sites for sodium channel toxins. The Na_v channel architecture shown here demonstrates the four domains, their six transmembrane domains and intracellular (bottom) and extracellular (top) structures. One of the key intracellular structures (indicated by orange spheres) is the inactivation gate. Superimposed on this diagram are the binding sites of key toxin tools. Figure reproduced from Klint JK, Senff S, Rupasinghe DB, et al. Spider-venom peptides that target voltage-gated sodium channels: Pharmacological tools and potential therapeutic leads. Toxicon 2012; 60:478–491 with permission from Elsevier.

Figure 2.

Venom and pain publication rate. Number of articles deposited in PubMed per year from 1970 to 2012 collated by the search term ‘pain AND (venom OR toxin)’.

Figure 3.

Venom and pain publication rate displayed separately. Number of articles deposited in PubMed per year from 1970 to 2012 showing separate search terms ‘pain’ (black circles) and ‘venom OR toxin’ (black triangles).

Figure 4.

The Trinidad chevron theraphosid (Psalmopoeus cambridgei) resting on a banana leaf, demonstrating the phenotype of these pharmacologically important spiders. Source: Photo by S Trim.

Figure 5.

Pre- and post-synaptic neurotoxin binding sites. Diagrammatic representation of the wealth of toxin tools known to bind ion channels and receptors pre- and post-synaptically. Figure reproduced from Casewell NR, Wüster W, Vonk FJ, et al. Complex cocktails: the evolutionary novelty of venoms. Trends Ecol Evol 2013; 28: 219–229 with permission from Elsevier.

Figure 6.

Quaternary distribution of theraphosid venom peptide sizes as deposited in UniProt, under the animal toxin annotation programme Tox-Prot.