Amide Chemistry Enables Redox Locking of Cyclic Disulfides for Polypeptide Assembly
Vincent Diemer1, Eliott Roy1, Benoît Snella1
1Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, Lille, F-59000, France.
Angewandte Chemie (International Ed. in English)
|June 24, 2025
Summary
Protecting thiol nucleophilicity with disulfides is key in organic synthesis. Acylating nearby amino groups dramatically stabilizes cyclic disulfides, enabling selective polypeptide assembly via redox switches.
Area of Science:
- Synthetic organic chemistry
- Redox chemistry
- Biochemistry
Background:
- Thiols are nucleophilic and often require temporary protection in synthesis.
- Disulfides are commonly used thiol protecting groups, exploiting redox properties.
- Disulfide stability can be sensitive to microenvironmental factors and nearby chemical modifications.
Purpose of the Study:
- To develop a method for significantly enhancing disulfide stability.
- To create a controllable redox switch for selective chemical reactions.
- To apply this strategy for chemoselective polypeptide assembly.
Main Methods:
- Conversion of thiols to cyclic disulfides.
- Acylation of an amino group proximal to the disulfide bond.
- Utilizing amide bond formation as a redox lock mechanism.
- Applying the developed redox switch in thiol-based peptide ligation.
Main Results:
- Acylation of a nearby amino group dramatically increased cyclic disulfide stability.
- Amide bond formation effectively created a stable redox lock.
- The redox switch enabled chemoselective polypeptide assembly.
- Demonstrated successful application in thiol-based peptide ligation.
Conclusions:
- Amide bond formation can act as a powerful redox lock, significantly enhancing disulfide stability.
- This strategy provides a practical means for achieving selectivity in systems with multiple thiol functionalities.
- The developed redox switch is applicable to chemoselective polypeptide synthesis.
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