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


Sauser, Luca; Kalvoda, Tadeáš; Kavas, Ayça; Rulíšek, Lubomír; Shoshan, Michal S (2022). Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification. ChemMedChem, 17(15):e202200152.

Abstract

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.

Abstract

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Scopus Subject Areas:Life Sciences > Biochemistry
Life Sciences > Molecular Medicine
Life Sciences > Pharmacology
Life Sciences > Drug Discovery
Life Sciences > General Pharmacology, Toxicology and Pharmaceutics
Physical Sciences > Organic Chemistry
Uncontrolled Keywords:Organic Chemistry, General Pharmacology, Toxicology and Pharmaceutics, Molecular Medicine, Drug Discovery, Biochemistry, Pharmacology
Language:English
Date:3 August 2022
Deposited On:17 Feb 2023 17:02
Last Modified:29 Mar 2024 02:40
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1860-7179
OA Status:Hybrid
Publisher DOI:https://doi.org/10.1002/cmdc.202200152
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)