Descripción del proyecto
Tecnología novedosa para identificar las dianas de fármacos naturales
Los avances en las tecnologías de la genómica y la metabolómica han reavivado las actividades de descubrimiento de fármacos empleando sustancias químicas naturales. Sin embargo, la identificación de dianas proteicas para estas nuevas moléculas bioactivas sigue siendo laboriosa. A fin de solucionar este problema, en el proyecto KavaTarget, financiado con fondos europeos, se diseñará una metodología novedosa para descubrir las dianas moleculares de moléculas pequeñas mediante el uso de unas sondas denominadas iBodies. Los investigadores del proyecto se centrarán en las propiedades bien documentadas contra la ansiedad de «Piper methysticum» o kava, un cultivo de las islas del Pacífico. Para validar su método, identificarán los receptores encefálicos y las enzimas de los hepatocitos que constituyen las principales dianas de estos metabolitos del kava. A largo plazo, la metodología de los iBodies ofrecerá la posibilidad de desarrollar tratamientos sin opioides de origen natural.
Objetivo
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)Coordinador
16610 Praha 6
Chequia