Identification of molecular targets of psychoactive kavalactones using iBodies

Informations projet

KavaTarget

N° de convention de subvention: 891397

DOI

10.3030/891397

Projet clôturé

Date de signature de la CE 9 Avril 2020

Date de début 1 Janvier 2021

Date de fin 30 Decembre 2024

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 156 980,64

Contribution de l’UE

€ 156 980,64

Coordonné par

USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I.
Czechia

Periodic Reporting for period 1 - KavaTarget (Identification of molecular targets of psychoactive kavalactones using iBodies)

Période du rapport: 2021-01-01 au 2022-12-31

Résumé du contexte et des objectifs généraux du projet

Advances in genomics and metabolomics technologies have rekindled drug discovery efforts using natural chemicals. However, the identification of protein targets of these new bioactive molecules remains laborious. To address this issue, the KavaTarget project aimed to design a novel methodology for discovering molecular targets of small molecules using innovative probes called iBodies. The project focused on metabolites with well-documented anti-anxiety properties from Piper methysticum or kava, a crop of the Pacific islands. The project aimed to validate the approach by identifying the brain receptors and hepatocyte enzymes that constitute primary targets of these kava metabolites. Although the project deviated from its original course during the implementation, it has contributed significantly to the development of metabolomics technologies and mapped new interactions between human receptors and small bioactive molecules from plants.

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

Over the course of the project, a high-throughput screening method for vanilloid-mediated activation of the human pain receptor TRPV1 was developed and used to characterize new capsaicinoids and their synergistic effects on the receptor. The project contributed significantly to the development of new metabolomics technologies, particularly related to the MZmine platform for mass spectrometry data processing. The originally envisioned iBodies approach failed due to the complexity of the linker chemistry, preventing progress in identifying brain or liver targets of kavalactones. However, the project overall resulted in 15 research publications or preprints. The project also helped with establishing new international collaborations and new research directions emerged, particularly in the areas metabolomics and machine learning applications to biochemistry.

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)

The project advanced our understanding of interactions between small molecules and human receptors, particularly for capsaicinoids derived from chili plants and their interactions with the human pain receptor TRPV1. On the technical level, the project helped deliver new methodologies and tools for computational metabolomics, particularly related to the MZmine project for mass spectrometry data processing.

The structure of HRP-iBodies loaded with capsaicin or RTX ligand.