KavaTarget · Identification of molecular targets of psychoactive kavalactones using iBodies
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-01-01 → 2024-12-30
- EU contribution
- €156,981
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Identification of molecular targets of psychoactive kavalactones using iBodies
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 KavaTarget project aimed to design a novel methodology for discovering molecular targets of small molecules using innovative probes called iBodies. The project focused on metabolites with well-documented anti-anxiety properties from Piper methysticum or kava, a crop of the Pacific islands. The project aimed to validate the approach by identifying the brain receptors and hepatocyte enzymes that constitute primary targets of these kava metabolites. Although the project deviated from its original course during the implementation, it has contributed significantly to the development of metabolomics technologies and mapped new interactions between human receptors and small bioactive molecules from plants.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- USTAV ORGANICKE CHEMIE A BIOCHEMIE, AV CR, V.V.I. · PRAHA 6CoordinatorCzechia
Links
Data: CORDIS, © European Union