A cyclodecapeptide ligand to vitamin B-12

Libraries of cyclic decapeptides were screened with vitamin B-12 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 similar to 10(5) M-1). Additional interactions between the peptide side chains and the vitamin B12 corrin moiety were determined by studying the H-1 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.