Description du projet
Une nouvelle technologie pour identifier des cibles médicamenteuses naturelles
Les avancées dans les technologies métabolomiques et génomiques ont relancé les efforts en matière de découverte de médicaments à l’aide de produits chimiques naturels. Toutefois, l’identification des cibles protéiques de ces nouvelles molécules bioactives reste laborieuse. Pour relever ce défi, le projet KavaTarget, financé par l’UE, concevra une nouvelle méthodologie pour découvrir des cibles moléculaires de petites molécules en utilisant des sondes innovantes appelées iBodies. Les chercheurs se concentreront sur des métabolites ayant des propriétés bien documentées contre l’anxiété issus de Piper methysticum ou kava, une plante cultivée aux îles du Pacifique. Ils valideront leur approche en identifiant les récepteurs cérébraux et les enzymes hépatocytes qui constituent les cibles primaires de ces métabolites du kava. À long terme, la méthodologie d’iBodies permettra de mettre au point des traitements non opiacés d’origine naturelle.
Objectif
Plant natural products have traditionally provided a great source of chemical scaffolds for the development of new medicines. Following a downturn in the late 20th century, natural product research is now experiencing a renaissance owing to rapid developments in genomics and metabolomics technologies. However, the identification of protein targets of newly discovered bioactive natural products remains very low-throughput. Under this proposal, I will carry out research to develop a new methodology for the elucidation of molecular targets of small bioactive molecules that bind to human proteins such as membrane receptors, using stochastically-generated polymeric probes called iBodies combined with horseradish peroxidase-mediated biotin labeling. In particular, I will focus on psychoactive metabolites from kava (Piper methysticum) called kavalactones, which have well-documented anti-anxiety properties, but their mechanism of action is unclear. In the first stage, I will develop the molecular target identification workflow using a previously characterized ligand, resiniferatoxin, which binds with high affinity to the human pain receptor TRPV1. Once the workflow is developed, I will proceed to identify the brain receptors that are the primary targets of natural kavalactones, as well as non-natural kavalactone derivatives that I recently developed. In addition, I propose that a similar approach can be applied to identify liver cytochrome P450 enzymes that are inhibited by natural products such as kavalactones. In the last stage of the project, I will develop a protocol for the extraction of liver proteins and identification of liver enzymes that interact with kavalactones. This research will deliver a new biochemical method for molecular target identification in the short term. In the long term, it will contribute to the development of novel non-opioid psychiatric therapeutics based on the kavalactone scaffold, thus addressing an urgent need in today’s European society.
Champ scientifique
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
16610 Praha 6
Tchéquie