1372875-14-3Relevant academic research and scientific papers
Femtomolar Ln(III) affinity in peptide-based ligands containing unnatural chelating amino acids
Niedzwiecka, Agnieszka,Cisnetti, Federico,Lebrun, Colette,Delangle, Pascale
, p. 5458 - 5464 (2012)
The incorporation of unnatural chelating amino acids in short peptide sequences leads to lanthanide-binding peptides with a higher stability than sequences built exclusively from natural residues. In particular, the hexadentate peptide P22, which incorporates two unnatural amino acids Ada2 with aminodiacetate chelating arms, showed picomolar affinity for Tb3+. To design peptides with higher denticity, expected to show higher affinity for Ln3+, we synthesized the novel unnatural amino acid Ed3a2 which carries an ethylenediamine triacetate side-chain and affords a pentadentate coordination site. The synthesis of the derivative Fmoc-Ed3a2(tBu)3-OH, with appropriate protecting groups for direct use in the solid phase peptide synthesis (Fmoc strategy), is described. The two high denticity peptides PHD2 (Ac-Trp-Ed3a 2-Pro-Gly-Ada2-Gly-NH2) and PHD5 (Ac-Trp-Ada2-Pro-Gly-Ed3a2-Gly-NH2) led to octadentate Tb3+ complexes with femtomolar stability in water. The position of the high denticity amino acid Ed3a2 in the hexapeptide sequence appears to be critical for the control of the metal complex speciation. Whereas PHD5 promotes the formation of polymetallic species in excess of Ln3+, PHD2 forms exclusively the mononuclear complex. The octadentate coordination of Tb3+ by both PHD leads to total dehydration of the metal ion in the mononuclear complexes with long luminescence lifetimes (>2 ms). Hence, we demonstrated that unnatural amino acids carrying polyaminocarboxylate side-chains are interesting building blocks to design high affinity Ln-binding peptides. In particular the novel peptide PHD2 forms a unique octadentate Tb3+ complex with femtomolar stability in water and an improvement of the luminescence properties with respect to the trisaquo TbP22 complex by a factor of 4.
