Toxin mimetics of human peptides as novel tools for drug discovery and design
Venomous animals use a myriad of toxins to specifically disrupt the physiology and behavior of their prey. Because of their high stability, potency, and specificity, toxins are important tools for biomedical research and have been developed as therapeutics for various human diseases. However, contributions to date pale in comparison to future prospects. We hypothesize that a small and essentially overlooked group of toxins, “ToxMims”, represent the most promising candidates for drug discovery and development. ToxMims potently disrupt the prey’s physiology by specifically mimicking the action of endogenous signaling peptides. Because many of these signaling peptides are critical players in human health and disease, ToxMims are exceptionally promising drug leads. Proof-of-concept is provided by our recent discovery of a toxin mimetic of insulin that is used by a marine cone snail to induce dangerously low blood sugar in fish prey. Because of its advantageous properties over human insulin, the venom insulin has rapidly become a novel drug lead for the treatment of diabetes. Despite their significant biomedical potential, ToxMims are rare and difficult to systematically detect using currently available methodologies. By leveraging recent advances in next-generation sequencing combined with our proven expertise in computational and experimental venom discovery and pharmacology, this project aims to develop a set of tools to enable the systematic identification and characterization of any ToxMim of the ~350 human signaling peptides with an emphasis on those implicated in disease. If successful, this research will not only identify a set of unique drug leads with profound impact on human health but elucidate previously unknown mechanisms of receptor activation, inhibition and signaling. Furthermore, this project will foster European excellence in venom research and develop scientific leadership competences for an independent, early-career researcher returning to Europe.