A cyclodecapeptide ligand to vitamin B12

Abstract

Libraries of cyclic decapeptides were screened with vitamin B₁₂ derivatives to give cyclic peptide ligands incorporating histidine and cysteine as coordinating residues and negatively charged amino acids. Two hits, cyclo-(HisAspGluProGlyIleAlaThrProDGln) and cyclo-(ValAspGluProGlyGluAspCysProDGln) were resynthesized in good yields for solution experiments. The peptides bind aquocobalamin with coordination of His or Cys to the cobalt with high affinities (K_a∼10⁵ M⁻¹). Additional interactions between the peptide side chains and the vitamin B₁₂ corrin moiety were determined by studying the ¹H NMR solution structure. The cyclopeptide–cobalamin complex with the histidine residue showed enhanced stability towards cyanide exchange, demonstrating the shielding effect of the ligand on the metal center.