Directing biosynthesis of bioactive triterpenes for pharmaceutical applications (OSBOURN_J18DTP)
- Research Area Industrial Biotechnology and Bioenergy
- Partner The John Innes Centre (JIC)
Professor Ann Osbourn -
- Application Deadline 27/11/2017
The triterpenes are one of the largest and most diverse classes of plant natural products, with many useful biological properties. Some naturally occurring triterpenes have weak anti-inflammatory activity and are promising drug leads. Synthetic derivatives with improved activity have been generated but selective functionalisation of triterpene scaffolds using conventional chemistry is problematic, and the modifications made were limited. Phase three clinical trials of the best known of these synthetic triterpenes, bardoxolone methyl, were recently terminated because of side effects.
Recent advances in triterpene biosynthesis are now opening up new opportunities to systematically direct biosynthesis and modification of different triterpene scaffolds using enzymes, making it possible to understand for the first time the relationship between triterpene structure and function, and the features that determine potency and selectivity. This project exploits an innovative synthetic biology approach for quick and easy biosynthesis of novel triterpenes in a transient plant expression system. Triterpene analogs will be evaluated for anti-proliferative and anti-inflammatory activity, and the underlying signalling pathways and targets investigated. Structure activity relationship analysis will determine the specific moieties necessary for bioactivity and inform the further generation of structurally related compounds.
During this project the student will gain a solid foundation in plant biotechnology, molecular biology, synthetic biology, natural product chemistry, bioinformatics and enzymology. He/she will also become proficient in mammalian cell biology including cell culture using a variety of human cell types, bioactivity assays, biochemistry and immunology.