Lead poisoning is still a problem that harms the health of many people. The current standard of care for treating lead poisoning involves chelating agents such as ethylenediaminetetraacetic acid (EDTA). However, these ligands lack metal selectivity, which can lead to the chelation and depletion of other, essential metal ions. Short peptides are versatile compounds that could be efficient and nontoxic alternatives to the ligands currently in use to treat lead poisoning.

Michal S. Shoshan, University of Zurich, Switzerland, and colleagues designed a cyclic peptide based on the natural peptide glutathione (GSH) for lead detoxification. The team used computationally aided rational design to enhance the activity of GSH. This enabled them to focus their synthetic efforts on specific peptides with higher probabilities of achieving high Pb binding affinities. Five chosen peptides were synthesized by solid-phase peptide synthesis, cyclized in solution, and then tested in vitro using lead-poisoned human cells.

The two best-performing peptides were thoroughly investigated using, e.g., UV/Vis spectroscopy, isothermal titration calorimetry, and high-resolution mass spectrometry (MS). The in vitro tests showed that the two peptides enhance Pb detoxication compared to GSH and also outperform the standard of care while being nontoxic. They have a high affinity for Pb²⁺ ions and capture them even with an excess of calcium and zinc ions. These results may lead to new options for modern chelation therapy.

• Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification,
  Luca Sauser, Tadeáš Kalvoda, Ayça Kavas, Lubomír Rulíšek, Michal S. Shoshan,
  ChemMedChem 2022.
  https://doi.org/10.1002/cmdc.202200152