Single stereocenter inversion of a cyclic tetrapeptide enables the detoxification of lead-exposed mice.

Lead (Pb) poisoning remains a global public health challenge, yet approved chelating agents are limited by poor selectivity, suboptimal efficacy, and safety concerns. We previously reported cyclic tetrapeptides as metal-binding therapeutics for Pb detoxification. The lead scaffold, containing two cysteines and two β-aspartic acid residues, showed high aqueous solubility but failed to rescue Pb-poisoned human cells. In this work, we conducted mechanistic studies revealing that diminished intrinsic Pb(ii) affinity and poor selectivity against competing Ca(ii) ions constrained its activity. Guided by these insights, we synthesized two analogs: one lacking a carboxylate and another with an inverted chiral center. Both analogs demonstrated markedly improved Pb detoxification in human cells, surpassing the efficacy of clinically used chelators. Strikingly, oral administration of the diastereomeric analog to Pb-exposed mice lowered blood Pb levels by 55-62% and increased urinary Pb excretion by up to 3-fold compared with vehicle or standard-of-care treatments. These findings illustrate how rational structure-activity relationship optimization can deliver selective, effective peptide-based chelators, establishing a promising therapeutic strategy against Pb poisoning.