Toxin mimetics of human peptides as novel tools for drug discovery and design

Informations projet

ToxMim

N° de convention de subvention: 949830

DOI

10.3030/949830

Projet clôturé le 14 Decembre 2023

Date de signature de la CE 10 Novembre 2020

Date de début 1 Janvier 2021

Date de fin 31 Decembre 2025

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 498 598,00

Contribution de l’UE

€ 1 498 598,00

Coordonné par

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 2 - ToxMim (Toxin mimetics of human peptides as novel tools for drug discovery and design)

Période du rapport: 2022-07-01 au 2023-12-31

Résumé du contexte et des objectifs généraux du projet

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. In this project aimed to study a small and essentially overlooked group of toxins, “ToxMims”. ToxMims 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. To effectively enable the discovery of new ToxMims for functional studies this project aimed to optimize computational tools to enable the identification of ToxMims from large venom datasets. Once identified, new ToxMims were synthesized and functionally characterized. Using these optimized tools, we identified a large class of toxins from venomous marine cone snails that mimic the human hormone somatostatin. These previously overlooked ToxMims are highly stable and selective for somatostatin receptors implicated in various human diseases, including cancer, pain, and neuroendocrine disorders.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The project began with the development of better computational methods to enable the discovery of novel ToxMims with therapeutic potential from large venom datasets. To this end we generated tools that specifically search for motifs that are conserved within human signaling peptides. We next used these tools to discover a large, previously unrecognized family of toxins from marine cone snails that mimic the human hormone somatostatin. These results were published in the journal Molecular Biology and Evolution in 2022. Interestingly, different toxins from this large family are selective for the different members of the human somatostatin receptor family. More detailed functional characterizations revealed that several of the new toxins target a receptor implicated in pain and others target receptors that are highly expressed in cancers of the neuroendocrine system. One of the toxins that has the potential to be developed into a new pain drug has been patented. Our discovery and characterization of this toxin will be published soon.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

An unexpected result of our project was that the discovery of a large family of toxins that mimic the human hormone somatostatin led us to investigate the evolution of this toxins family. These studies revealed that the somatostatin signaling system is broadly found in many animal phyla and, contrary to the existing dogma, represents one of the most ancient signaling systems in animals. This observation suggested that we can use ToxMims to discover previously unknown signaling peptides. Inspired by this finding we systematically demonstrated that the venoms of cone snails can be used to identify novel signaling peptides. The results of this study were published in 2023 in the journal Frontiers in Molecular Neuroscience.

Venomous snails of the superfamily Conoidea studied in this project