Summary
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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More information & hyperlinks
| Web resources: | https://cordis.europa.eu/project/id/891397 |
| Start date: | 01-01-2021 |
| End date: | 30-12-2024 |
| Total budget - Public funding: | 156 980,64 Euro - 156 980,00 Euro |
Cordis data
Original description
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.Status
SIGNEDCall topic
MSCA-IF-2019Update Date
28-04-2024
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