Directing biosynthesis of bioactive triterpenes for pharmaceutical applications
Lead Research Organisation:
University of East Anglia
Department Name: Graduate Office
Abstract
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.
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.
Organisations
People |
ORCID iD |
| Anne Osbourn (Primary Supervisor) | |
| Rebecca Casson (Student) |
| Description | The chemical space of triterpene biosynthesis has been expanded by this research, allowing for a greater number and diversity of triterpenes to be synthesised. New bioactive triterpenes have been discovered, and greater insight gained into the features responsible for triterpene bioactivity. |
| Exploitation Route | Pharmaceutically active triterpenes developed as a result of this study could be taken forwards into further testing and eventually clinical trials. The expanded chemical space of triterpene biosynthesis may be utilised in the future manufacture of triterpenes for commercial purposes. |
| Sectors | Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | Annual Science Meeting Student Poster 2019 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | As part of the annual institute science meeting, I produced and presented a poster on my research to the wider institute, including postgraduate students, postdoctoral researchers, group leaders, and research assistants. This led to productive discussions on my work with other postgraduates. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Annual Science Meeting Student Poster 2020 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | As part of the institute's annual science meeting, held online, I produced a poster that was available for the entire institute, with an audience including other postgraduate students, postdoctoral researchers, group leaders, and research assistants. The poster was available in an online format for a week before a discussion session was held in which I was able to discuss my research with other postgraduate students. |
| Year(s) Of Engagement Activity | 2020 |
| Description | Annual Science Meeting Student Poster 2021 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | As part of the institute's annual science meeting, I produced a poster that was available for the entire institute, with an audience including other postgraduate students, postdoctoral researchers, group leaders, and research assistants. The poster was displayed along with others for the duration of the three-day meeting, with discussion sessions held in the lunch periods, in which I was able to discuss my research with other postgraduate students, postdoctoral scientists, and group leaders, many of them outside of my department and who were interested in my work. |
| Year(s) Of Engagement Activity | 2021 |
| Description | Departmental Seminar 2020 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | A presentation of the work carried out and major findings obtained in the first 18 months of the project was given to an audience consisting of interested researchers including project leaders, postgraduate and postdoctoral researchers, and research staff, both from within the department and across the wider institution. The presentation led to a lively discussion with many questions being asked and answered, and additional perspectives arose which assisted with the development of future research directions. |
| Year(s) Of Engagement Activity | 2020 |
| Description | Departmental Seminar 2021 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | A presentation of the work carried out and major findings obtained over the course of the project so far was given to an audience consisting of interested researchers including project leaders, postgraduate and postdoctoral researchers, and research staff, both from within the department and across the wider institution. The presentation led to a lively discussion with many questions being asked and answered, and additional perspectives arose which assisted with the development of future research directions. |
| Year(s) Of Engagement Activity | 2021 |
| Description | Departmental Seminar 2022 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | A presentation of the work carried out and major findings obtained over the course of the project overall was given to an audience consisting of interested researchers including project leaders, postgraduate and postdoctoral researchers, and research staff, both from within the department and across the wider institution. The presentation led to a lively discussion with many questions being asked and answered, and additional perspectives arose which assisted with the development of future research directions. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Norwich Cancer Research Network Symposium 2022 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Postgraduate students |
| Results and Impact | I participated in the 'flash talks' section of the Norwich Cancer Research Network's 2022 symposium, explaining my research in 3 minutes using only 2 slides to an audience including UEA students, staff, and researchers drawn from across the Norwich Research Park, including the Norwich Bioscience Institutes and the hospital. Although relevant to the fields of drug discovery and cancer research, my focus on plant biosynthesis of active molecules was a novelty to many of the attendees, leading to numerous discussions after the talks. |
| Year(s) Of Engagement Activity | 2022 |
| Description | Norwich Science Festival 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Myself and a few colleagues from JIC and UEA ran a stand at the 2019 science festival introducing the public to triterpenes and some of their potential applications. The stand ran for the entire day, during which hundreds of interested visitors came and went, including many families with children, as the event took place during the October half-term. The children really engaged with the concept of building their own "triterpene" out of lego blocks, and reported an increased enthusiasm for science, while the stand sparked a number of discussions with adults on biotechnology in general. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Norwich Science Festival 2021 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Myself and a few colleagues from JIC and UEA ran a stand at the 2021 science festival introducing the public to triterpenes and some of their potential applications, as well as their origins in plants and why they are produced in nature. The stand ran for the entire day, during which hundreds of interested visitors came and went, including many families with children, as the event took place during the October half-term. The children really engaged with the concept of building their own "triterpene" and enzymes out of lego blocks, and reported an increased enthusiasm for science, while the stand sparked a number of discussions with adults on biotechnology in general, as well as specific issues such as genetic modification. |
| Year(s) Of Engagement Activity | 2021 |
| Description | Norwich Science Festival 2023 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Myself and colleagues from UEA ran a stand at the 2023 science festival focusing on the biochemistry of cancer and related research. The stand ran for the entire day, during which hundreds of interested visitors came and went, including many families with children, as the event took place during the February half-term. The children really engaged with the concept of cancer as "rogue cells" and how scientists aim to treat it without harming healthy cells, and reported an increased enthusiasm for science, while the stand sparked a number of discussions with adults on cancer prevention and treatment, my research into drug discovery, as well as more generally about biotechnology and biochemistry. |
| Year(s) Of Engagement Activity | 2023 |
| Description | UEA WISE Conference 2021 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Undergraduate students |
| Results and Impact | As part of the UEA WISE society's international women's day events, I took part in a half-day series of talks alongside other women in science, talking about our research. The audience consisted of undergraduate and postgraduate students from the UEA as well as staff and interested members of the public, comprising ~30-40 people on a rotating basis. My presentation sparked discussion about my research, my career path, and science in general. |
| Year(s) Of Engagement Activity | 2021 |