A Cysteine Selenosulfide Redox Switch for Protein Chemical Synthesis

26 February 2020, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


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.


cyclic selenosulfide
cysteine surrogate
SEA-mediated reactions
SEA-mediated ligation
Reaction mechanism
Native Chemical Ligation
C-N bond cleavage
Peptide synthesis
Chemical protein synthesis
hepatocyte growth factor
cyclic proteins
tyrosine kinase activity
Cell scattering
AlphaScreen assay
Reaction Kinetic Studies
One-Pot Approach
Redox Switch

Supplementary materials

SupportingInformation R1 3


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.