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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 todays European society.

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Programme(s)

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Topic(s)

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Funding Scheme

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.

(opens in new window) H2020-MSCA-IF-2019

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Coordinator

USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I.
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 156 980,64
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 156 980,64
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