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.

Department of Chemistry University of Zurich Winterthurerstrasse 190 8057 Zurich Switzerland

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo náměstí 2 16610 Praha 6 Czech Republic

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World Health Organization, Lead Poisoning and Health, 2019.

Skerfving S., Bergdahl I. A. Handbook on the Toxicology of Metals, Elsevier, 2012, 911–956.

Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological Profile of Lead, 2007. PubMed

Mason L. H., Harp J. P., Han D. Y., BioMed Res. Int. 2014, 2014, 840547. PubMed PMC

Tangahu B. V., Sheikh Abdullah S. R., Basri H., Idris M., Anuar N., Mukhlisin M., Int. J. Chem. Eng. 2011, 2011, 939161.

Flora S. J. S., Al Ameen J. Med. Sci. 2009, 2, 4–26.

P. B. Tchounwou, C. G. Yedjou, A. K. Patlolla, D. J. Sutton, Molecular, Clinical and Environmental Toxicology. 2012.

Dudev T., Grauffel C., Lim C., Inorg. Chem. 2018, 57, 14798–14809. PubMed

Flora S. J. S., Pachauri V., Int. J. Environ. Res. Public Health 2010, 7, 2745–2788. PubMed PMC

Flora G., Gupta D., Tiwari A., Interdiscip. Toxicol. 2012, 5, 47–58. PubMed PMC

Engwa G. A., Ferdinand P. U., Nwalo F. N., Unachukwu M. N., Poisoning in the Modern World - New Tricks for an Old Dog?, IntechOpen, 2019, 1–128.

Lowry J. A., The Children's Mercy Hospitals and Clinics, Kansas City, 2010.

Kaličanin B., Rašić M. T., J. Heavy. Met. Toxicity. Dis. 2019, 4, 2 : 5.

Sears M. E., Sci. World J. 2013, 2013, 219840. PubMed

Kim J. J., Kim Y. S., Kumar V., J. Trace Elem. Med. Biol. 2019, 54, 226–231. PubMed

Ellis M. R., Kane K. Y., Am. Fam. Physician 2000, 62, 545–554. PubMed

Mohammed T. A., Meier C. M., Kalvoda T., Kalt M., Rulíšek L., Shoshan M. S., Angew. Chem. Int. Ed. 2021, 60, 12381–12385. PubMed

Sauser L., Mohammed T. A., Kalvoda T., Feng S. J., Spingler B., Rulíšek L., Shoshan M. S., Inorg. Chem. 2021, 60, 18620–18624. PubMed

Alcaro M. C., Sabatino G., Uziel J., Chelli M., Ginanneschi M., Rovero P., Papini A. M., J. Pept. Sci. 2004, 10, 218–228. PubMed

Jensen K. J., Peptide and Protein Design for Biopharmaceutical Applications 2009.

Gutten O., Rulíšek L., Inorg. Chem. 2013, 52, 10347–10355. PubMed

See Supporting Information.

Mah V., Jalilehvand F., Inorg. Chem. 2012, 51, 6285–6298. PubMed PMC

Jacquart A., Brayner R., El Hage Chahine J. M., Ha-Duong N. T., Chem.-Biol. Interact. 2017, 267, 2–10. PubMed

Savjani K. T., Gajjar A. K., Savjani J. K., ISRN Pharmcol. 2012, 2012, 195727. PubMed PMC

V. Cangelosi, L. Ruckthong, V. L. Pecoraro, Lead: It's Effects on Environment and Health 2017

All but 2 and 9 were fully cyclized (see Supporting Information). The reactions were monitored by LCMS.

Peptides 2, 5, and 8 were added as tetrasodium salts to improve their solubility.

Feoktistova M., Geserick P., Leverkus M., Cold Spring Harb. Protoc. 2016, 2016, 343–346. PubMed

Chang C. A., Liu Y. L., Chen C. Y., Chou X. M., Inorg. Chem. 2001, 40, 3448–3455. PubMed

Buist D., Williams N. J., Reibenspies J. H., Hancock R. D., Inorg. Chem. 2010, 49, 5033–5039. PubMed

Brechbiel M. W., J. Nucl. Med. 2008, 52, 166–173. PubMed PMC

Shoshan M. S., Tshuva E. Y., Chem. Eur. J. 2016, 22, 9077–9081. PubMed

Shoshan M. S., Lehman Y., Goch W., Bal W., Tshuva E. Y., Metanis N., Org. Biomol. Chem. 2016, 14, 6979–6984. PubMed

Wu D., Yotnda P., J. Visualization 2011, 57, 3357.

Rousselot-Pailley P., Sénèque O., Lebrun C., Crouzy S., Boturyn D., Dumy P., Ferrand M., Delangle P., Inorg. Chem. 2006, 45, 5510–5520. PubMed

A shift in the absorption maximum of the LMCT band is associated with a change in coordination around the Pb(II) ion.

Jalilehvand F., Sisombath N. S., Schell A. C., Facey G. A., Inorg. Chem. 2015, 54, 2160–2170. PubMed PMC

Bracaglia, Physiol. Behav. 2017, 176, 139–148. PubMed PMC

Duan L., Kong J. J., Wang T. Q., Sun Y., BioMetals 2018, 31, 539–550. PubMed

Sisombath N. S., Jalilehvand F., Schell A. C., Wu Q., Inorg. Chem. 2014, 53, 12459–12468. PubMed PMC

J. Aaseth, O. Andersen, Chelation Therapy in the Treatment of Metal Intoxication 2016.

Riener C. K., Kada G., Gruber H. J., Anal. Bioanal. Chem. 2002, 373, 266–276. PubMed

Design of Zn-Binding Peptide(s) from Protein Fragments