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  Combining yeast chemical genetics and Artificial Intelligence to identify molecules from plants and fungi with modes-of-action relevant to cancer and Parkinson’s disease.


   London Interdisciplinary Biosciences Consortium

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  Dr T Prescott, Dr B Panaretou  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this project please visit the LIDo website: https://www.lido-dtp.ac.uk/apply

This is a multidisciplinary project that will combine in silico and cell-based screening with molecular genetic techniques and natural product chemistry to rapidly identify plant and fungal molecules that are specific inhibitors of mis-regulated proteins associated with disease in humans.

Large living and preserved collections of plants and fungi, such as those found at Kew, represent an extremely valuable resource for drug discovery, but identifying pharmacologically selective molecules from nature that exhibit desirable modes-of-action is currently both time consuming and inefficient. Natural products chemistry needs new efficient approaches to unlock the medicinal potential of plant and fungal compounds and ensure that only compounds with specific and potent pharmacological activity undergo chemical isolation. The aim of this project is to test the ability of an artificial intelligence cheminformatics platform to correctly predict which compounds out of all published plant and fungal metabolites, interact selectively with specific drug targets.

The in vivo screening platform will be yeast cells genetically modified in such a way as to render them hypersensitive to inhibitors of our selected drug targets, i) the kinase mTOR and the molecular chaperone Hsp90, both of which contribute to the development of tumours. and ii) the Parkinson’s disease drug target a-synuclein. In addition, the screening platform will be genetically modified so that it lacks drug efflux pumps and increases membrane permeability, thereby overcoming the drug resistance mechanisms that have restricted drug discovery in the past.

Additional confirmation of selectivity will be achieved by creating a panel of yeast deletion strains diagnostic for off-target non-receptor activities that are common in plants and have undesirable effects on human cell physiology. Plant and fungal extracts obtained from living material at Kew Gardens will be assessed using this screening system and target molecules exhibiting promising activities will be chemically isolated at the Jodrell laboratory at Kew. Molecules with selective inhibition profiles will then be validated in human cell lines using commercially available kits for highly sensitive detection of mTOR and Hsp90 activity, and a-synuclein toxicity.

This interdisciplinary project will provide training in plant and fungal natural product chemistry, chemoinformatics and chemical genetics.


Funding Notes

Fully funded place including home (UK) tuition fees and a tax-free stipend in the region of £17,609.
LIDo has a maximum of 11 fully funded opportunities for students eligible for overseas fees.

References

A yeast chemical genetics approach identifies the compound 3,4,5-trimethoxybenzyl isothiocyanate as a calcineurin inhibitor. Prescott TA, Panaretou B, Veitch NC, Simmonds MS. (2013) FEBS Letters 588(3):455-458
A Mini HIP HOP Assay Uncovers a Central Role for Copper and Zinc in the Antifungal Mode of Action of Allicin. Prescott, TAK and Panaretou B (2017) Journal of Agricultural and Food Chemistry. 65:3659-3664
Yeast Chemogenomic Profiling Reveals Iron Chelation To Be the Principle Cell Inhibitory Mode of Action of Gossypol. Prescott TAK, Jaeg T and Hoepfner D. (2018) Journal of Medicinal Chemistry. 61: 7381-7386