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Solid Phase Synthesis of Short Peptide-Based Multimetal Tags for Biomolecule Labeling

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Department of Chemistry, Humboldt-Universitaet zu Berlin, Brook-Taylor-Strasse 2, 12489 Berlin, Germany
*Tel: +(49) 30 2093 7575, Fax: +(49) 30 2093 6985. E-mail: [email protected]
Cite this: Bioconjugate Chem. 2014, 25, 6, 1069–1077
Publication Date (Web):May 15, 2014
Copyright © 2014 American Chemical Society

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    We describe an unprecedented solid phase peptide synthesis (SPPS) of short peptide-based multimetal tags designated as elemental tags for the quantification of biomolecules via inductively coupled plasma mass spectrometry (ICP-MS). The macrocyclic chelator 1,4,7,10-tetraazacyclododecane N,N′,N″,N‴-tetra acetic acid (DOTA) was attached to the side chain of N-α-(9-fluorenylmethoxycarbonyl)-l-lysine (Fmoc-Lys-OH) and metalated with a lanthanide to provide a building block for Fmoc-based SPPS. Thereby, in contrast to existing strategies for the synthesis of DOTA–peptide conjugates, an already metalated DOTA-amino acid was used as a building block for SPPS. The DOTA-lanthanide complex was stable throughout the whole SPPS, even during the final cleavage in concentrated trifluoroacetic acid. This indicates that the strategy to first metalate the Fmoc-Lys(DOTA)-OH and to utilize the metal coordination to protect the carboxyl groups of DOTA offers an alternative to conventional synthetic routes using tert-butyl protected DOTA. Several small peptides containing up to four metal ions were synthesized, among them peptides carrying defined metal sequences consisting of two different lanthanides. The peptides were N-terminally maleimide-functionalized, thus introducing a moiety for conjugation to thiol-bearing biomolecules. The final objective of this work was the signal enhancement in ICP-MS-based DNA quantification assays. To evaluate the performance of the multimetal peptide tags in assay, they were applied to label thiol-modified 15mer DNA oligonucleotide probes. These served as reporter probes in a model sandwich-type hybridization assay. Thereby, we found that the ICP-MS signal increased linearly with the number of lanthanide ions attached to the reporter probe.

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    HPLC-UV and HPLC-HRMS data of compound 3; copies of 1H, 13C NMR spectra of compound 4; HPLC-UV traces and HPLC-HRMS data for the peptides (5–10); CID fragmentation pattern for the peptides 6, 8, 9, 10. This material is available free of charge via the Internet at

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    Cited By

    This article is cited by 9 publications.

    1. Zhian Hu, Gongwei Sun, Wencan Jiang, Fujian Xu, Yuqing Zhang, Mengchan Xia, Xingyu Pan, Zhi Xing, Sichun Zhang, Xinrong Zhang. Chemical-Modified Nucleotide-Based Elemental Tags for High-Sensitive Immunoassay. Analytical Chemistry 2019, 91 (9) , 5980-5986.
    2. Jan Kretschmer, Tomáš David, Martin Dračínský, Ondřej Socha, Daniel Jirak, Martin Vít, Radek Jurok, Martin Kuchař, Ivana Císařová, Miloslav Polasek. Paramagnetic encoding of molecules. Nature Communications 2022, 13 (1)
    3. Daniel Torregrosa, Guillermo Grindlay, Luis Gras, Juan Mora. Immunoassays based on inductively coupled plasma mass spectrometry detection: So far so good, so what?. Microchemical Journal 2021, 166 , 106200.
    4. Liam Connah, Goran Angelovski. Solid phase synthesis in the development of magnetic resonance imaging probes. Organic Chemistry Frontiers 2020, 7 (24) , 4121-4141.
    5. Pablo Lores Lareo, Michael W. Linscheid, Oliver Seitz. Nucleic acid and SNP detection via template‐directed native chemical ligation and inductively coupled plasma mass spectrometry. Journal of Mass Spectrometry 2019, 54 (8) , 676-683.
    6. Michael W. Linscheid. Molecules and elements for quantitative bioanalysis: The allure of using electrospray, MALDI, and ICP mass spectrometry side-by-side. Mass Spectrometry Reviews 2019, 38 (2) , 169-186.
    7. Shixi Zhang, Sichun Zhang, Xinrong Zhang, Rui Liu. Analysis of Proteins and DNAs Using Inductively Coupled Plasma Mass Spectrometry and Elemental Tagging. 2018, 1-45.
    8. Thomas C. de Bang, Søren Husted. Lanthanide elements as labels for multiplexed and targeted analysis of proteins, DNA and RNA using inductively-coupled plasma mass spectrometry. TrAC Trends in Analytical Chemistry 2015, 72 , 45-52.
    9. Sandrine Lamandé-Langle, Charlotte Collet, Raphaël Hensienne, Christine Vala, Françoise Chrétien, Yves Chapleur, Amel Mohamadi, Patrick Lacolley, Véronique Regnault. ‘Click’ glycosylation of peptides through cysteine propargylation and CuAAC. Bioorganic & Medicinal Chemistry 2014, 22 (23) , 6672-6683.

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