Lead (Pb) is a ubiquitous poisonous metal, affecting the health of vast populations worldwide. Medications to treat Pb poisoning suffer from various limitations and are often toxic owing to insufficient metal selectivity. Here, we report a cyclic tetrapeptide that selectively binds Pb and eradicates its toxic effect on the cellular level, with superior potency than state‐of‐the‐art drugs. The Pb‐peptide complex is remarkably strong and was characterized experimentally and computationally. Accompanied by the lack of toxicity and enhanced stability of this peptide, these qualities indicate its merit as a potential remedy for Pb poisoning.

The natural tripeptide glutathione (GSH) is a ubiquitous compound harboring various biological tasks, among them interacting with essential and toxic metal ions. Yet, although weakly binding the poisonous metal lead (Pb), GSH poorly detoxifies it. β-Mercaptoaspartic acid is a new-to-nature novel amino acid that was found to enhance the Pb-detoxification capability of a synthetic cyclic tetrapeptide. Aiming to explore the advantages of noncanonical amino acids (ncAAs) of this nature, we studied the detoxification capabilities of GSH and three analogue peptides, each of which contains at least one ncAA that harbors both free carboxylate and thiolate groups. A thorough investigation that includes in vitro detoxification and mechanistic evaluations, metal-binding affinity, metal selectivity, and computational studies shows that these ncAAs are highly beneficial in additively enhancing Pb binding and reveals the importance of both high affinity and metal selectivity in synergistically reducing Pb toxicity in cells. Hence, such ncAAs join the chemical toolbox against Pb poisoning and pollution, enabling peptides to strongly and selectively bind the toxic metal ion.

Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10. 1002/anie.202109786.Scheme 1. Retrosynthesis of shagenes A and B. Angewandte Chemie CommunicationsScheme 3. Stereoselectivity of diastereoselective double-bond isomerization and relative thermodynamic stabilities of intermediates calculated by Spartan 18 at the wB97X-D/6-31G* level of theory.

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