The integration of peptides and proteins with bismuth presents novel opportunities for drug discovery. Unlike most heavy metals, bismuth is non-toxic and has a long history of safe use in over-the-counter medications such as Pepto-Bismol. Additionally, the radioactive isotope 213Bi is a promising alpha-particle emitter for targeted cancer therapy. Despite these advantages, the direct incorporation of bismuth into peptides and proteins remains underexplored.
Bismuth–peptide bicycles define a new class of metallopeptides, where a single bismuth atom is coordinated by three cysteine residues. This constrained structure enhances peptide rigidity, resulting in potent protein binders and inhibitors. When integrated with phage display, this chemistry enables the high-throughput discovery of bismuth–peptide bicycles targeting proteins of interest.
We have introduced peptide–bismuth bicycles as a novel class of cell-penetrating peptides that efficiently cross human cell membranes at nanomolar concentrations, demonstrating significantly enhanced permeability compared to conventional linear cell-penetrating peptides such as TAT and R8. The incorporation of bismuth enforces a constrained conformation, improving cellular uptake by orders of magnitude relative to their linear counterparts.
By engineering a related binding motif into a single-domain antibody (nanobody), we demonstrate an alternative to conventional bifunctional linkers for theranostic applications. This strategy allows direct coordination of medically relevant metals such as bismuth (for TAT), indium (for SPECT), and gallium (for PET). Metal uptake occurs instantaneously upon reduction, and the resulting nanobodies remain stable and functionally active for several days.