Biocatalytic Diversification of Complex Natural Products for Enhanced Therapeutic Performance (EL-DEMERDASH_U26CASE)
Many natural products (NPs) show remarkable biological activity, yet their clinical potential is often limited by poor solubility, metabolic instability, or toxicity. These issues stem from the rigid, hydrophobic, and synthetically challenging frameworks typical of complex NPs. In this project, we aim to overcome these limitations by using biocatalysis, a green and highly selective method to modify natural products at otherwise inert positions. This interdisciplinary project will apply state-of-the-art biocatalysts, including cytochrome P450s, hydroxylases, and flavin-dependent halogenases, to selectively modify three high-value natural products:
• Plumbagin – A naphthoquinone with potent anticancer activity.
• Lithocholic acid – A bile acid with emerging neuroprotective effects.
• Camptothecin – A clinically relevant anticancer agent targeting Topoisomerase I.
In collaboration with Prozomix Ltd. (an industrial leader in enzyme development), this project will:
1. Establish a tailored enzyme panel for site-selective late-stage functionalization of complex NP scaffolds.
2. Optimize biocatalytic reactions to generate a focused library of new NP analogues.
3. Evaluate their anticancer and neuroprotective activities in human cell-based assays.
4. Generate SAR data linking specific enzymatic modifications to pharmacological properties.
This PhD project offers extensive research training in:
• Biocatalysis and enzyme screening.
• Natural product derivatization and purification.
• Analytical chemistry (NMR, LC-MS, HPLC)
• Mammalian cell-based pharmacology.
• Multidisciplinary collaboration (chemical biology and pharmacology).
The student will also undertake a three-month placement at Prozomix Ltd., gaining industrial experience in enzyme production, assay design, and biocatalytic process development. This project is ideally suited for a student with a background in biological chemistry, medicinal chemistry, biochemistry, or related disciplines, and a keen interest in enzyme-enabled drug discovery.