A cysteine selenosulfide redox switch for protein chemical synthesis

Vincent Diemer (1) , Nathalie Ollivier (2) , Bérénice Leclercq , Hervé Drobecq (1) , Jérôme Vicogne (1) , Vangelis Agouridas (3) , Oleg Melnyk (1)

1 IBL - Institut de biologie de Lille - UMS 3702
2 CBF - Chemical Biology of Flatworms [Lille]
3 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204

The control of cysteine reactivity is of paramount importance for the synthesis of proteins using the native chemical ligation (NCL) reaction. We report 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 describe that N-selenoethyl cysteine (SetCys) loses its selenoethyl arm in water under mild conditions upon reduction of its selenosulfide bond. Detailed mechanistic investigations show that the cleavage of the selenoethyl arm proceeds through an anionic mechanism with assistance of the cysteine thiol group. The implementation of the SetCys unit 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.

Domaines: Chimie organique; Chimie thérapeutique

Vincent Diemer, Nathalie Ollivier, Bérénice Leclercq, Hervé Drobecq, Jérôme Vicogne, et al.. A cysteine selenosulfide redox switch for protein chemical synthesis. Nature Communications, 2020, 11, pp.2558. ⟨10.1038/s41467-020-16359-6⟩. ⟨hal-02734393⟩