Potent Cyclic Tetrapeptide for Lead Detoxification

Mohammed, Tagwa A.; Meier, C.; Kalvoda, Tadeáš; Kalt, Martina; Rulı́s̆ek, Lubomı́r; Shoshan, Michal S.

doi:10.1002/anie.202103217

Cited by 8 publications

(17 citation statements)

References 34 publications

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“…Remarkably, 2 and 3 outcompete the benchmark drugs against Pb poisoning, ethylenediaminetetraacetic acid and dimercaptosuccinic acid, because these compounds recovered 95 ± 16% and 110 ± 4% of the cells, respectively. 15 Furthermore, the results also reflect a synergistic effect S3. The titration curves were fitted to a oneset-of-sites binding model to all peptides, but 3 was fitted with a two-set-of-sites model using Origin software; UV-monitored back-titrations of peptide−Pb(II) complexes (100 μM) with ZnCl 2 (0.1−1 mM; 1−10 equiv; E) or CaCl 2 (1−10 mM; 10−100 equiv; F).…”

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confidence: 99%

“…We recently revealed the potential of de novo cyclic tetrapeptides to detoxify Pb(II) ions in human cells by tightly and selectively binding them . While initially the metal-binding residues were Cys and Asp, we found that replacing the former with the novel noncanonical amino acid (ncAA) β-mercaptoaspartic acid (β S Asp; X) enhanced the solubility of the leading peptide and its metal affinity, metal selectivity, and detoxification capabilities . These findings are attributed to the chelate effect within this hybrid ligand that binds Pb(II) ion via the carboxylate and thiolate upon deprotonation, forming a stable five-membered ring.…”

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confidence: 99%

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Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities

et al. 2021

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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.

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confidence: 99%

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Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities

et al. 2021

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“…This peptide was found to be superior to the Cys-containing peptide, with improved characteristics in every tested aspect: higher potency in recovering Pb-contaminated cells, lack of toxicity, enhanced affinity, and metal selectivity. [26] It was also found stable toward oxidation and degradation for 48 h in human blood serum, while the Cys-containing peptide underwent oxidation in a similar setup. [26] These results indicate the great promise that ncAAs also hold toward pharmaceutical purposes.…”

Section: Peptide Siderophoresmentioning

confidence: 92%

“…[26] It was also found stable toward oxidation and degradation for 48 h in human blood serum, while the Cys-containing peptide underwent oxidation in a similar setup. [26] These results indicate the great promise that ncAAs also hold toward pharmaceutical purposes.…”

Section: Peptide Siderophoresmentioning

confidence: 92%

“…Although nature utilizes peptides and proteins to control metal poisoning, [24] and it is already established that peptides and artificial AAs can achieve excellent metal affinity and selectivity, this potential application is overlooked. [25] We recently explored a family of cyclic tetrapeptides for their ability to detoxify Pb 2+ ions [26] as one of the most harmful metals to human health. [27] At first, the peptides were composed of only proteinogenic coordinating AAs: Cys, Asp, Met, and His, where one peptide excelled to a greater extent recovering Pb-poisoned human cells.…”

Section: Heavy Metal Detoxificationmentioning

confidence: 99%

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Enhancing Metal-binding with Noncanonical Coordinating Amino Acids

Sauser

Shoshan

2021

Chimia

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More than 50% of proteinogenic amino acid sidechains can bind metal ions, enabling proteins and peptides to bear these ions as cofactors. Nevertheless, post-translational modifications and incorporation of noncanonical amino acids bestow peptides and proteins myriads of other coordination capabilities, thanks to an enhanced metal binding. Here we summarize selected examples of natural and artificial systems that contain one or more noncanonical amino acids coordinating a metal ion and subsequently achieve a new or enhanced function. We report on a wide array of systems: from disease-related proteins that undergo sulfurylation or phosphorylation through natural metallophores that selectively capture precious essential ions to synthetic selfassembly strategies, biocatalysts, and chelating agents against toxic metals. Regardless of their (bio)synthetic routes, all possess unique metal-binding properties that could not be effectively achieved by systems composed of canonical residues.

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Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification

et al. 2022

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A rationally‐designed scaffold of cyclic octapeptides composed of two units of the natural tripeptide glutathione (GSH) was optimized to strongly and selectively capture toxic lead ions (Pb(II)). Using state‐of‐the‐art computational tools, a list of eleven plausible peptides was shortened to five analogs based on their calculated affinity to Pb(II) ions. We then synthesized and investigated them for their abilities to recover Pb‐poisoned human cells. A clear pattern was observed from the in vitro detoxification results, indicating the importance of cavity size and polar moieties to enhance metal capturing. These, together with the apparent benefit of cyclizing the peptides, improved the detoxification of the two lead peptides by approximately two folds compared to GSH and the benchmark chelating agents against Pb poisoning. Moreover, the two peptides did not show any toxicity and, therefore, were thoroughly investigated to determine their potential as next‐generation remedies for Pb poisoning.

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Potent Cyclic Tetrapeptide for Lead Detoxification

Cited by 8 publications

References 34 publications

Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities

Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities

Enhancing Metal-binding with Noncanonical Coordinating Amino Acids

Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification

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