Design of MRI contrast agents based on designed metallo coiled coils

About the Project

This PhD project will develop a new class of MRI contrast agents. MRI is an essential tool for medical diagnosis. Contrast agents play a crucial role in improving the images obtained, and hence patient outcomes. Most clinical MRI contrast agents are based on gadolinium, due to its electronic structure. However, gadolinium toxicity is a recognised problem for patients and our environment. This project will take inspiration from biology to design, synthesize and study, miniature artificial protein scaffolds (easily prepared on an automated peptide synthesiser), for use as ligands for paramagnetic metal ions. We have previously shown that when coordinated to gadolinium, these complexes are more “efficient”, better than clinical agents.[1] Through peptide redesign it has been possible to further enhance performance.[2] More recently, we reported for the first time that copper, previously entirely disregarded for use in MRI contrast agent design, is better than clinical agents when coordinated to these ligands.[3] This was previously thought to be impossible! Using a biologically essential metal ion (essential for correct biological function), such as copper, is exciting as our bodies already know how to process and remove trace amounts of these metals if needed. Unlike gadolinium which will accumulate in the body over time.

The project will develop new miniature protein-inspired ligands, based on coiled coils, for use in MRI contrast agent design, and will be ideal for students that are interested in inorganic chemistry and synthetic biology. Training will be gained in (computational) peptide design, synthesis, characterisation, metal binding evaluation and MRI. Including, but not limited to, solid-phase peptide synthesis, HPLC and biophysical characterisation techniques (e.g., native MS, UV-visible, fluorescence and CD spectroscopy, X-ray protein crystallography).

This PhD studentship is based in the group of Professor Anna Peacock at the University of Birmingham in the state-of-the-art £80M Molecular Sciences Building. Interested candidates with (or nearing completion of) a good (1st of 2.1 UK or equivalent) degree in chemistry or the biological sciences should apply via https://www.birmingham.ac.uk/schools/chemistry/phd/apply.aspx. Applications will be considered on an ongoing basis until a suitable candidate has been appointed. Interested candidates should contact Professor Anna Peacock for informal enquiries, and before applying should provide a CV and cover letter summarising their research interests and previous experience. For more information, please see https://peacockresearch.wordpress.com

The School of Chemistry at the University of Birmingham is keen to achieve a gender and diversity balance, and welcomes and encourages applicants from all backgrounds.

Funding Notes

This fully-funded studentship includes stipend and tuition fees for UK students paid at the UKRI level. Support for conference attendance and research costs will be available.

References

[1] Berwick et al “De Novo Design of Ln(III) Coiled Coils for Imaging Applications” J. Am. Chem. Soc., 2014, 136, 1166
[2] Berwick et al “Location dependent coordination chemistry and MRI relaxivity in de novo designed lanthanide coiled coils” Chem. Sci., 2016, 7, 2207
[3] Shah et al “Design of the elusive proteinaceous oxygen donor copper site suggests a promising future for copper for MRI contrast agents“, Proc. Natl. Acad. Sci., USA., 2023, 120, e2219036120.