Exploring the toxic potential of marine crustaceans for drug development

Many animals use poisons for self-defense or for hunting. The components of such poisons, so-called toxins, intervene in various physiological processes – which is why they are so interesting for the development of new pharmacological active ingredients. While the venoms of some groups of animals – including snakes, spiders, scorpions and insects – are already quite well studied, the situation for groups of marine animals is completely different. Since data is only available for individual animal species, this group still has great untapped potential.

Only a few years ago it was discovered that there are also poisonous crustaceans, i.e. remipeders, which look more like millipedes and live underwater in sea caves. A multidisciplinary research team led by Dr. Björn von Reumont, who first described the venom system in Remipedes in 2014 and is currently a visiting researcher at the Goethe University Frankfurt, has now characterized a group of toxins from Remipedes Xibalbanus tulumensis remipede.

Reumont put together a team consisting of cooperation partners from the Fraunhofer Institute for Translational Medicine (ITMP) as part of the LOEWE Center for Translational Biodiversity as well as colleagues from the University of Leuven, Cologne, Berlin and Munich – all of whom are also part of the European Venom Network (COST Action EUVEN).

The Xibalbanus tulumensis Remipede lives in the cenotes, the underwater cave systems on Mexico's Yucatan Peninsula. The cave dweller injects the poison produced in its poison gland directly into its prey. This toxin contains a variety of components, including a new type of peptide called xibalbin after its crustacean producer. Some of these xibalbins contain a characteristic structural element known from other toxins, especially from spiders: several amino acids (cysteines) of the peptide are bound together in such a way that they form a knot-like structure. This in turn makes the peptides resistant to enzymes, heat and extreme pH values. Such knottins often act as neurotoxins, interacting with ion channels and paralyzing prey – an effect that has also been suggested for some xibalbins.

The study shows that all xibalbin peptides tested by the cooperation partners' doctoral students – and in particular Xib₁Xib₂ and Xib₁₃ – Effectively inhibit potassium channels in mammalian systems. “This inhibition is of great importance when it comes to developing drugs for a range of neurological diseases, including epilepsy,” says von Reumont. Xib₁ and Xib₁₃ also have the ability to inhibit voltage-gated sodium channels, such as those found in nerve or cardiac muscle cells. In addition, in the sensory neurons of higher mammals, the two peptides can activate two proteins – the kinases PKA-II and ERK1/2 – that are involved in signal transduction. The latter suggests that they are involved in pain sensitization, which opens up new approaches in pain therapy.

Although the bioactivity of xibalbins exemplifies the untapped potential of marine biodiversity, producing medicines from animal venoms is a complex and time-consuming process. “Today, finding suitable candidates, comprehensively characterizing their effects and thus laying the foundation for safe and effective medications is only possible in a large interdisciplinary team like in the case of our study,” says von Reumont.

To make matters worse, time is of the essence for the Remipedes. Their habitat is seriously threatened by the construction of the Tren Maya intercity railway network, which runs across the Yucatan Peninsula. “The cenotes are a highly sensitive ecosystem,” explains von Reumont, who, as an experienced cave diver, has collected remipedes in the Yucatan on several cave diving expeditions. “Our study highlights the importance of protecting biodiversity, not only because of its ecological importance, but also because of potential substances that could be of crucial importance to us humans.”