Invited Talk 21st International Conference on Biological Inorganic Chemistry 2025

Advancing MRI Contrast Agent Design with Metallo Coiled Coils (122189)

Anna FA Peacock 1
  1. University of Birmingham, Edgbaston, WEST MIDLANDS, United Kingdom

We report the engineering of a new-to-biology proteinaceous copper site within a designed coiled coil scaffold, capable of unanticipated function, thereby expanding and enhancing the protein design toolbox.[1]

Copper ion sites are extremely common in biology and perform diverse roles ranging from electron transfer to oxygen transport. Its biological coordination chemistry is equally diverse, ranging from exclusive nitrogen coordination, exclusive sulfur coordination and mixed NxSyOz sites. Given that copper bound exclusively to oxygen donors is relatively common in inorganic chemistry, it remains surprising that there are no such proteinaceous copper sites in biology.

We report the preparation and characterization of the first example of the elusive proteinaceous CuOx site, using a designed coiled coil protein scaffold.[1] That begs the question, what properties may this new-to-biology metal ion site possess? We have previously demonstrated that the relaxivity (“efficiency”) of gadolinium(III) (a metal routinely used in MRI contrast agents) is greatly enhanced on complexation to our designed coiled coils, and that performance can be predictably tuned through de novo peptide design strategies.[2,3] This copper(II) coiled coil is capable of even higher relaxivity values, that are better than current clinical agents. This was previously thought to be impossible! The high relaxivity of this new copper(II) complex challenges the existing and as we demonstrate, mistaken dogma, that copper(II) with a single unpaired electron, is unsuitable for use in MRI contrast agents due to poor relaxivity!

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Figure. De novo designed copper coiled coil.

We describe a strategy by which new-to-biology functional metal ion sites can be accessed within protein scaffolds, thereby expanding the toolbox from which protein/peptide designers can select in their efforts to achieve the holy grail of synthetic biology - realizing new function beyond the repertoire of biology. 

 

[1] A. Shah et al., Proc. Natl. Acad. Sci., USA. 2023, 120, e2219036120

[2] M. R. Berwick et al., J. Am. Chem. Soc. 2014, 136, 1166-1169.

[3] A. M. Webster, A. F. A. Peacock, Chem. Commun. 2021, 57, 6851-6862.