Bismuth-Selenium Peptides and Proteins: Thermodynamic Stability Meets Kinetic Inertness for Medicinal Applications

Bismuth peptides and proteins show significant potential as future drug candidates and radiotherapeutics. Bismuth(III) binds three cysteine residues in peptides and proteins with remarkable selectivity. While the thermodynamic stability of these bismuth peptides and proteins is outstanding, their kinetic lability limits clinical applications to date. Introducing bismuth selenopeptides, we demonstrate that selenocysteine binds bismuth with much higher kinetic stability than cysteine. We determine this effect by directly comparing a peptide with three cysteine residues with an identical peptide containing three selenocysteines. While incubation with the strong metal chelator ethylenediaminetetraacetic acid (EDTA) at equimolar concentration for one hour resulted in 50% bismuth displacement in the cysteine peptide, its selenocysteine analog required one week of incubation with 100 equivalents of EDTA to achieve the same level of bismuth displacement. We observed a similar trend for the protein epidermal growth factor (EGF) comprising three disulfide bonds. We established that precisely two bismuth atoms bind to the six cysteine or selenocysteine residues in EGF and seleno-EGF, respectively, and found that bismuth-seleno-EGF is kinetically inert compared to the bismuth-EGF complex. Overall, we demonstrate that bismuth-selenium peptides and proteins possess sufficient thermodynamic stability and kinetic inertness for future medicinal applications.