Primary Supervisor: Dr Melanie Britton, School of Chemistry
Secondary supervisor: Dr Anna Peacock
PhD project title: Artificial metalloproteins as novel MRI contrast agents
University of Registration: University of Birmingham
Since MRI’s first clinical applications nearly thirty years ago, MRI has become an essential tool for clinical diagnosis. Image contrast is routinely enhanced by the use of a contrast agent (CA), with the overwhelming majority based on complexes of gadolinium, and more recently manganese.
However, current MRI CAs are limited by their small size (limits relaxivity, MRI efficiency) and inability to interact with biomolecules in a targeted fashion. In contrast, proteins satisfy both of these limitations, and thus, the goal of this project is to replace the ligands associated with traditional MRI CAs, with protein ligands.
Preliminary results have found that gadolinium complexes of miniature coiled coil protein scaffolds, see Figure, display superior MRI contrast capabilities compared to the traditional small molecular complexes currently employed in the clinic. This project will build on these findings, by engineering similar gadonlium (and manganese) sites into small proteins such as the family of knottin proteins (see Figure), and larger assemblies with appropriate targeting opportunities.
Figure 1 Cartoon representation of miniature A) coiled coil, or B) knottin, protein scaffolds, into which gadolinium and manganese sites will be engineered for use as MRI contrast agents.
This project builds on a long-term collaboration between the Peacock and Britton groups, bringing together expertise in peptide and protein design, synthesis and characterisation (Peacock) with MRI application and development (Britton). This powerful synergy will offer the student the opportunity to become expert in the broadest range of techniques and skills.
- [Berwick, M. R.; Lewis, D. J.; Pikramenou, Z.; Jones, A. W.; Cooper, H. J.; Wilkie, J.; Britton, M. M.; Peacock, A. F. A.“De Novo Design of Ln(III) Coiled Coils for Imaging Applications” J. Am. Chem. Soc., 2014, 136, 1166.
- Berwick, M. R.; Slope, L. N.; Smith, C.; King, S. M.; Newton, S. L.; Gillis, R; Adams, G.; Rowe, A.; Harding, S.; Britton, M. M.; Peacock, A. F. A. “Location dependent coordination chemistry and MRI relaxivity, in de novo designed lanthanide coiled coils” Chem. Sci., 2016, 7, 2207.
- Slope, L. N.; Hill, M. G.; Smith, C. F.; Teare, P.; de Cogan, F. J.; Britton, M. M.; Peacock, A. F. A. “Tuning Coordination Chemistry Through the Second Sphere in Designed Metallocoiled Coils” Chem. Comm., 2020, 56, 3729-3732.
- V. C. Pierre, et al., J. Biol. Inorg. Chem., 2014, 19, 127.
- Zastrow, M.; Peacock, A. F. A.; Stuckey, J.; Pecoraro, V. L. “Hydrolytic Catalysis and Structural Stabilization in a Designed Metalloprotein” Nature Chem., 2012, 4, 118.
BBSRC Strategic Research Priority: Renewable Resources and Clean Growth: Industrial Biotechnology & Understanding the Rules of Life: Structural Biology & Integrated Understanding of Health: Pharmaceuticals
Techniques that will be undertaken during the project:
Training and experience will be gained in magnetic resonance imaging and relaxivity measurements, protein design, synthesis, biophysical characterisation techniques including, but not limited to, gel electrophoresis, ultraviolet-visible and circular dichroism spectroscopy.
Contact: Dr Melanie Britton, University of Birmingham