The design of metal ion chelators is an active field of research which aims at synthesizing efficient molecules either for chelation therapy, which is used in case of metal intoxication and to treat disorders of metal homeostasis, or for the preparation of metal-based probes. In RICC team, we are developing ligands derived from natural molecules, more specifically peptides, to take advantage of the amazing biological properties of proteins. This strategy allowed us to synthesize copper ligands with even better chelation properties than copper transporters, and to obtain lanthanide binding peptides combining some properties of the natural scaffold with the magnetic or photophysical properties of the metal ion.
Copper chelators derived from intracellular Cu(I) transporters. Metal overload plays an important role in several diseases or intoxications. Among these metals, copper (Cu) is an essential element which intracellular concentration needs to be rigorously controlled so that it does not accumulate to toxic levels. Biological molecules which are trafficking or sequestering Cu in cells are good models to design efficient Cu chelators. Many intracellular Cu transporters contain a conserved N-terminal MXCXXC sequence that binds metal ions with two cysteines. A cyclodecapeptide (PC in Fig. 1) that mimics the binding loop of the copper chaperone Atx1 and contains this highly conserved amino acid sequence has been demonstrated to be highly selective for Cu(I) vs. the essential ion Zn(II).
Recently, Cu(I) chelators of high affinity and selectivity were obtained by anchoring three cysteines on a polyaminocarboxylate scaffold. The tripodal pseudopep-tide ligand L (Fig. 1), provides three soft sulfur donors and mimics the selectivity of metallothioneins or other cysteine-rich proteins for the soft ions Cu(I) and Hg(II).
Lanthanide-peptide complexes. Lanthanide (Ln) ions find potential applications in biomedical sciences, for instance paramagnetic Gd complexes as contrast agents for MRI or Tb and Eu complexes as long-lived luminescent probes. The development of Ln complexes derived from peptides is especially promising as these complexes are expected to combine the attractive properties of the lanthanide cation with those of the biological scaffold, like hydrophilicity or biomolecular recognition. A cyclodecapeptide incorporating two prolyl-glycine sequences as β-turn inducers and carrying four side chains with carboxylate groups for metal complexation (PA in Fig. 2) has been designed in our team. This template adopts a conformation, suitable to complex Ln(III), with an orientation of its carboxyl groups on the same face of the peptide scaffold. The stability of its Ln complexes is similar to those obtained with natural Ln-binding peptides: (logβ(LnPA) » 6.5). Moreover, as expected several second-sphere water molecules are H-bonded to this very hydrophilic peptide complex and significantly contribute to the water relaxivity which is the key parameter of MRI contrast agents.
The affinity of peptides derived from natural amino acids remains low. Therefore efficient lanthanide-binding peptides (for instance P in Fig. 2) including unnatural chelating amino acids with aminodiacetate side-chains are currently developed. In these complexes, the stability can be enhanced by a synergy between metal coordination and the establishment of peptide secondary structure elements, like β-turns and hydrophobic interactions.
Selected publication(s) A. Pujol et al, J. Am. Chem. Soc. 131 (2009) 6928; A. Pujol et al, J. Am. Chem. Soc. 133 (2011) 286; A. Pujol et al, Chem. Eur. J. 17 (2011) 4418; A. Pujol et al, Angew. Chem. Int. Ed. 51 (2012) 7445; C.S. Bonnet et al, Chem. Eur. J. 15 (2009) 7083; F. Cisnetti et al., Chem. Eur. J. 15 (2009) 7456; A. Niedźwiecka et al; Inorg. Chem. 51 (2012) 5458
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