Medicinal Chemistry & Chemical Biology, Contributed Talk (15min)

Cyclic Tetrapeptides: Novel Remedy for Lead Poisoning

T. A. Mohammed1, C. M. Meier1, L. Rulíšek2, M. S. Shoshan1*
1University of Zurich, Department of Chemistry, Winterthurerstrasse 190, 8057 Zurich, 2Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry, Flemingovo nμmeˇstí 2, 16610 Praha 6

Lead (Pb) is the most abundant toxic metal that causes significant ecological and medicinal issues. The primary approach to address Pb poisoning is by chelation therapy, in which a chelating agent that can coordinate and remove the poisonous metal is administered. To date, there is no ideal chelating agent for treating Pb toxicity, and the available chelating agents lack metal selectivity. Hence, they are highly toxic themselves and subsequently prohibited from treating the most affected population segments, including children and pregnant women.[1]

Nature harnessed peptides and proteins for handling metal poisoning.[2] Inspired by natural systems, we designed and synthesized a family of cyclic tetrapeptides.[3] We examined their ability to recover Pb-poisoned bacteria and human cells, where two candidates showed a prominent potency, outcompeting the current clinical chelating agents. Investigating the Pb-peptide complex of the lead ligand experimentally and computationally disclosed its surpassing metal affinity and selectivity. In addition, we carried out an in vivo mice study, which revealed its outstanding chelating ability and promising potential to be a novel antidote for Pb poisoning.

[1] Nicholas Rees, Richard Fuller, UNICEF and Pure Earth. 2020.
[2] Christopher Cobbett, Peter Goldsbrough, Annu. Rev. Plant Biol. 2002, 53, 159-182.
[3] Tagwa A. Mohammed, Christoph M. Meier, Tadeáš Kalvoda, Martina Kalt, Lubomír Rulíšek, Michal S. Shoshan, Angew. Chem. Int. Ed. 2021, 60, 12381-12385.