Photo-responsive supramolecular ion transporters
Lead Research Organisation:
University of Oxford
Abstract
Ion transport across lipid bilayer membranes is a key process in biology, facilitated by transmembrane proteins that act as channels and pumps. The activity of these proteins is regulated by external stimuli, including small molecule signalling molecules, membrane potential and light. Ion transporting proteins also find numerous biotechnological applications, ranging from synthetic cell development to optogenetics. The significant interest in designing synthetic systems able to transport ions across cell membranes is driven by the pressing need for new therapeutics for treating channelopathies (diseases arising from mis-regulated ion transport processes) such as cystic fibrosis, and novel chemical tools for diagnostics and biotechnological applications. Designing ion transporters that are responsive to external stimuli, and thus able to be dynamically controlled with spatio-temporal precision, is key to targeted applications. However, such stimuli-responsive transporters are extremely rare and there are no general design criteria to inform the development of such systems.
In this project we aim to develop artificial mobile ion carriers that can be controlled by light. Ion carriers are molecules which can freely diffuse across lipid bilayer membranes, and transport ions through a bind and release mechanism. They are attractive alternatives to membrane proteins because they are relatively simple to synthesise, considerably more "drug-like", and inherently adaptable to target the desired stimulus and ion cargo. Our primary objectives are to (i) develop novel supramolecular ion carriers with built-in photo- responsive behaviour, and whose activity can be modulated in response to different wavelengths of light, (ii) develop robust design criteria necessary for the design of stimuli- response ion transporters, and (iii) explore the application of photo-controlled transporters in biological contexts.
We will design and synthesise new classes of photo-responsive ion carriers and study their activity and mechanism in detail using liposome-based assays, before applying our best functioning systems in artificial and living cells. Stimuli-responsive artificial carriers, which can be both targeted and activated remotely for precise spatio-temporal control over ion transport, are highly desirable molecular targets. Success in this area is likely to impact widely in the areas of targeted therapeutics and tools for synthetic biology.
This interdisciplinary project falls within the EPSRC research areas of synthetic supramolecular chemistry, synthetic organic chemistry and synthetic coordination chemistry, identified as areas to "maintain", and the "grow" area of chemical biology.
In this project we aim to develop artificial mobile ion carriers that can be controlled by light. Ion carriers are molecules which can freely diffuse across lipid bilayer membranes, and transport ions through a bind and release mechanism. They are attractive alternatives to membrane proteins because they are relatively simple to synthesise, considerably more "drug-like", and inherently adaptable to target the desired stimulus and ion cargo. Our primary objectives are to (i) develop novel supramolecular ion carriers with built-in photo- responsive behaviour, and whose activity can be modulated in response to different wavelengths of light, (ii) develop robust design criteria necessary for the design of stimuli- response ion transporters, and (iii) explore the application of photo-controlled transporters in biological contexts.
We will design and synthesise new classes of photo-responsive ion carriers and study their activity and mechanism in detail using liposome-based assays, before applying our best functioning systems in artificial and living cells. Stimuli-responsive artificial carriers, which can be both targeted and activated remotely for precise spatio-temporal control over ion transport, are highly desirable molecular targets. Success in this area is likely to impact widely in the areas of targeted therapeutics and tools for synthetic biology.
This interdisciplinary project falls within the EPSRC research areas of synthetic supramolecular chemistry, synthetic organic chemistry and synthetic coordination chemistry, identified as areas to "maintain", and the "grow" area of chemical biology.
Planned Impact
This programme is focused on a new cohort-driven approach to the training of next-generation doctoral scientists in the practice of novel and efficient chemical synthesis coupled with an in-depth appreciation of its application to biology and medicine.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
This collaborative academic-industrial SBM CDT will have long-term benefit to the chemical industry, including the pharmaceutical, agrochemical and fine chemical sectors. These industries will benefit through: (i) the potential to employ individuals trained with broad and relevant scientific and transferable skills; (ii) new approaches to the investigation of complex biological and medical problems through novel chemistry; and (iii) better and more efficient synthetic methods.
We will link the work of DSTL, and our pharmaceutical and agrochemical partners (GSK, UCB, Vertex, Evotec, Eisai, AstraZeneca, Syngenta, Novartis, Takeda, Sumitomo and Pfizer) through a common theme of synthesis training. The design and synthesis of new compounds is essential for disease treatment and prevention, and for maintaining food security. Synthesis contributes significantly to UK tax revenue and results in sustained employment across a number of sectors. Employers in the finance, law, health, academic, analytical, government, and teaching professions, for example, also recognise the value of the translational skill-sets possessed by synthesis postgraduates, which this programme will provide.
The SBM CDT training programme will adopt an IP-free model to enable completely free exchange of information, know-how and specific expertise between students and supervisors on different projects and across different industrial companies. This will lead to better knowledge creation through unfettered access to information from all academics, partners and students involved in the project. By focussing on basic science, we will engender genuine collaboration leading to enabling technology that will be of use across a wide range of industries.
We will train the next generation of multidisciplinary synthetic chemists with an appreciation of the impact of synthesis in biology and medicine. Their unconstrained view of synthesis will aid in new scientific discoveries leading to new products, which (with appropriate inward investment), can lead to the formation of new companies and new UK employment.
We will, in part through an alliance with the Defence, Science and Technology Laboratory, engage with policy-makers to influence future policy issues involving chemistry such as food security and the rise of antibiotic resistance (both of which are relevant to our programme and are important for society as a whole).
Outreach and public engagement will be a key aspect of our programme; and all students in the proposed SBM CDT will take part in at least one outreach activity. Typical activities include: open days in the Chemistry Department through the 'Outreach Alchemists', engaging with the Oxfordshire Science Festival and participation in the various other activities already in place through the public engagement programme of the Department of Chemistry.
The research output of the students will be disseminated via high impact international publications and lectures; these will be of value to other academics in relevant fields and will be of value in the development of further research funding applications. Outreach activities and research output will also be advertised on a website dedicated to the proposed SBM programme.
