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A Cysteine Selenosulfide Redox Switch for Protein Chemical Synthesis

preprint
revised on 26.02.2020 and posted on 26.02.2020 by Vincent Diemer, Nathalie Ollivier, Bérénice Leclercq, Hervé Drobecq, Jérôme Vicogne, Vangelis Agouridas, Oleg Melnyk
The control of cysteine reactivity is of paramount importance for the synthesis of proteins using the native chemical ligation (NCL) reaction. We discovered that this goal can be achieved in a traceless manner during ligation by appending a simple N-selenoethyl group to cysteine. While in synthetic organic chemistry the cleavage of carbon-nitrogen bonds is notoriously difficult, we found that N-selenoethyl cysteine (SetCys) loses its selenoethyl arm in water under mild conditions upon reduction of its selenosulfide bond. Detailed mechanistic investigations uncover a novel mode of reactivity for Cys. Its implementation in a process enabling the modular and straightforward assembly of linear or backbone cyclized polypeptides is illustrated by the synthesis of biologically active cyclic hepatocyte growth factor variants.

Funding

ANR-19CE07-0020

History

Email Address of Submitting Author

oleg.melnyk@ibl.cnrs.fr

Institution

CNRS, Université de Lille, INSERM, Institut Pasteur de Lille

Country

France

ORCID For Submitting Author

0000-0002-3863-5613

Declaration of Conflict of Interest

The authors declare no competing interests.

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