Descrizione del progetto
Una nuova tecnologia per l’individuazione di bersagli farmaceutici naturali
I progressi ottenuti nelle tecnologie di genomica e metabolomica hanno riacceso i tentativi volti alla scoperta di farmaci mediante l’impiego di sostanze chimiche naturali. Ciononostante, l’individuazione delle proteine bersaglio di queste nuove molecole bioattive resta laboriosa. Per affrontare tale problema, il progetto KavaTarget, finanziato dall’UE, progetterà una nuova metodologia per la scoperta dei bersagli molecolari di piccole molecole che impiega sonde innovative, chiamate iBodies. I ricercatori concentreranno l’attenzione sui metaboliti dotati di proprietà ansiolitiche ben documentate originati dalla kava (Piper methysticum), una coltura diffusa nelle isole del Pacifico. Gli studiosi convalideranno il proprio approccio individuando i recettori cerebrali e gli enzimi epatociti che costituiscono i principali bersagli di questi metaboliti della kava. A lungo termine, la metodologia basata su iBodies offrirà l’opportunità di sviluppare terapie di origine naturale che non prevedono l’utilizzo di oppiacei.
Obiettivo
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)Coordinatore
16610 Praha 6
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