Volume 30, Issue 15 e202304050
Research Article

Gold-Promoted Biocompatible Selenium Arylation of Small Molecules, Peptides and Proteins

Dr. Douglas H. Nakahata

Dr. Douglas H. Nakahata

Donostia International Physics Center – DIPC, Paseo Manuel de Lardizabal 4, 20018 Donostia, Euskadi, Gipuzkoa, Spain

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Ioannis Kanavos

Ioannis Kanavos

Institut des Sciences Analytiques et de Physico-Chimie Pour l'Environnement et les Matériaux – IPREM, E2S UPPA, CNRS, Université de Pau et des Pays de l'Adour, 64053 Pau, France

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Dr. Maria Zubiria-Ulacia

Dr. Maria Zubiria-Ulacia

Donostia International Physics Center – DIPC, Paseo Manuel de Lardizabal 4, 20018 Donostia, Euskadi, Gipuzkoa, Spain

Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea Euskal Herriko Unibertsitatea UPV/EHU, Donostia, Spain, Euskal Herriko Unibertsitatea UPV/EHU, Paseo Manuel de Lardizabal 3, 20018 Donostia, Euskadi, Gipuzkoa, Spain

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Alex Inague

Alex Inague

Biochemistry Department, Institute of Chemistry, University of São Paulo, São Paulo, 05508000 SP, Brazil

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Prof. Luca Salassa

Prof. Luca Salassa

Donostia International Physics Center – DIPC, Paseo Manuel de Lardizabal 4, 20018 Donostia, Euskadi, Gipuzkoa, Spain

Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea Euskal Herriko Unibertsitatea UPV/EHU, Donostia, Spain, Euskal Herriko Unibertsitatea UPV/EHU, Paseo Manuel de Lardizabal 3, 20018 Donostia, Euskadi, Gipuzkoa, Spain

Ikerbasque, Basque Foundation for Science, Plaza Euskadi 5, 48009 Bilbao, Euskadi, Bizkaia, Spain

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Prof. Ryszard Lobinski

Prof. Ryszard Lobinski

Institut des Sciences Analytiques et de Physico-Chimie Pour l'Environnement et les Matériaux – IPREM, E2S UPPA, CNRS, Université de Pau et des Pays de l'Adour, 64053 Pau, France

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Prof. Sayuri Miyamoto

Prof. Sayuri Miyamoto

Biochemistry Department, Institute of Chemistry, University of São Paulo, São Paulo, 05508000 SP, Brazil

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Prof. Jon Mattin Matxain

Prof. Jon Mattin Matxain

Donostia International Physics Center – DIPC, Paseo Manuel de Lardizabal 4, 20018 Donostia, Euskadi, Gipuzkoa, Spain

Polimero eta Material Aurreratuak: Fisika, Kimika eta Teknologia, Kimika Fakultatea Euskal Herriko Unibertsitatea UPV/EHU, Donostia, Spain, Euskal Herriko Unibertsitatea UPV/EHU, Paseo Manuel de Lardizabal 3, 20018 Donostia, Euskadi, Gipuzkoa, Spain

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Dr. Luisa Ronga

Dr. Luisa Ronga

Institut des Sciences Analytiques et de Physico-Chimie Pour l'Environnement et les Matériaux – IPREM, E2S UPPA, CNRS, Université de Pau et des Pays de l'Adour, 64053 Pau, France

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Dr. Raphael E. F. de Paiva

Corresponding Author

Dr. Raphael E. F. de Paiva

Donostia International Physics Center – DIPC, Paseo Manuel de Lardizabal 4, 20018 Donostia, Euskadi, Gipuzkoa, Spain

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First published: 10 January 2024

Graphical Abstract

Organometallic gold(III) compounds are introduced here as a valuable addition to the toolkit of metal-based systems apt at facilitating selenium arylation, with applications spanning from synthetic chemistry to selenoprotein modification. By combining multinuclear NMR, LC–MS and DFT we show that the compound [Au(bnpy)Cl2] enables the arylation of diselenides and selenols present in small molecules, peptides, and proteins via a redox-based mechanism.

Abstract

A low pKa (5.2), high polarizable volume (3.8 Å), and proneness to oxidation under ambient conditions make selenocysteine (Sec, U) a unique, natural reactive handle present in most organisms across all domains of life. Sec modification still has untapped potential for site-selective protein modification and probing. Herein we demonstrate the use of a cyclometalated gold(III) compound, [Au(bnpy)Cl2], in the arylation of diselenides of biological significance, with a scope covering small molecule models, peptides, and proteins using a combination of multinuclear NMR (including 77Se NMR), and LC–MS. Diphenyl diselenide (Ph−Se)2 and selenocystine, (Sec)2, were used for reaction optimization. This approach allowed us to demonstrate that an excess of diselenide (Au/Se−Se) and an increasing water percentage in the reaction media enhance both the conversion and kinetics of the C−Se coupling reaction, a combination that makes the reaction biocompatible. The C−Se coupling reaction was also shown to happen for the diselenide analogue of the cyclic peptide vasopressin ((Se−Se)-AVP), and the Bos taurus glutathione peroxidase (GPx1) enzyme in ammonium acetate (2 mM, pH=7.0). The reaction mechanism, studied by DFT revealed a redox-based mechanism where the C−Se coupling is enabled by the reductive elimination of the cyclometalated Au(III) species into Au(I).

Conflict of interests

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.