Projektbeschreibung
Natürliche Wirkstofftargets finden – mit neuartiger Technologie
Durch Fortschritte in Technologien für Genomik und Metabolomik hat der Einsatz natürlicher Chemikalien bei der Arzneimittelentwicklung neuen Auftrieb gewonnen. Doch noch immer ist es sehr aufwendig, Proteintargets dieser neuen bioaktiven Moleküle zu identifizieren. Darum wird das EU-finanzierte Projekt KavaTarget jetzt mit innovativen Sonden, den sogenannten iBodies, eine neue Methode entwickeln, um molekulare Targets in niedermolekularen Verbindungen auszumachen. Im Mittelpunkt stehen dabei Stoffwechselprodukte der südpazifischen Pflanze Piper methysticum (oder Kava), deren beruhigende Wirkeigenschaften bereits gut dokumentiert sind. Validiert wird der Forschungsansatz durch Identifikation der spezifischen Hirnrezeptoren und Leberenzyme, die die primären Angriffspunkte dieser Kava-Stoffwechselprodukte bilden. Langfristig wird es dank der iBodies-Methode möglich sein, opioidfreie Therapeutika natürlichen Ursprungs herzustellen.
Ziel
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.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
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