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Identification of molecular targets of psychoactive kavalactones using iBodies

Project description

A novel technology for the identification of natural drug targets

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 EU-funded KavaTarget project will design a novel methodology for discovering molecular targets of small molecules using innovative probes called iBodies. Researchers will focus on metabolites with well-documented anti-anxiety properties from Piper methysticum or kava, a crop of the Pacific islands. They will validate their approach by identifying the brain receptors and hepatocyte enzymes that constitute primary targets of these kava metabolites. Long term, the iBodies methodology will offer the opportunity to develop non-opioid therapeutics of natural origin.

Objective

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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Coordinator

USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I.
Net EU contribution
€ 156 980,64
Address
Flemingovo nam. 542/2
16610 Praha 6
Czechia

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Region
Česko Praha Hlavní město Praha
Activity type
Research Organisations
Links
Other funding
€ 0,00