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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
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Strained Cyclic Disulfides Enable Cellular Uptake by Reacting with the Transferrin Receptor
Daniel Abegg1, Giulio Gasparini1, Dominic G Hoch1
1School of Chemistry and Biochemistry, National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva , CH-1211 Geneva, Switzerland.
Journal of the American Chemical Society
|December 22, 2016
Summary
A new asparagusic acid tag (AspA tag) enables efficient cellular uptake of unprotected peptides. This method delivers peptides to cancer cells, inducing apoptosis via transferrin receptor targeting.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Efficient delivery of therapeutic peptides into cells remains a challenge.
- Unprotected peptides often suffer from poor stability and limited cellular penetration.
- Targeted delivery systems are crucial for enhancing therapeutic efficacy and reducing off-target effects.
Purpose of the Study:
- To develop a novel, efficient method for cellular peptide delivery.
- To investigate the mechanism of uptake for peptides tagged with asparagusic acid.
- To utilize this delivery system for inducing apoptosis in cancer cells.
Main Methods:
- Attachment of a single asparagusic acid residue (AspA tag) to peptides.
- Application of AspA-tagged peptides for inducing apoptosis in cancer cells using BH3 domain peptides.
- Chemical proteomics to identify molecular targets of the AspA tag.
- Investigation of the interaction between the AspA tag and the transferrin receptor.
Main Results:
- The AspA tag ensures efficient cellular uptake and intracellular distribution of unprotected peptides.
- AspA-tagged BH3 domain peptides successfully induced apoptosis in cancer cells.
- Covalent bond formation between the AspA moiety and cysteines 556/558 on the transferrin receptor was identified as the uptake mechanism.
- Transferrin receptor-mediated endocytic uptake of the AspA-tagged payload was confirmed.
Conclusions:
- The AspA tag is a small, non-toxic, and highly efficient peptide delivery system.
- The tag utilizes the transferrin receptor for targeted cellular entry.
- This method holds significant promise for various life science applications, including cancer therapy.
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