Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 54, Issue 25, Pages 7328-7331Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201502358
Keywords
cell-penetrating peptides; cellular uptake; dihedral angles; disulfides; ring tension
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Funding
- University of Geneva
- European Research Council (ERC)
- National Centre of Competence in Research (NCCR) Chemical Biology
- NCCR Molecular Systems Engineering
- Swiss NSF
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The objective of the study was to explore the potential of ring tension in cyclic disulfides for thiol-mediated cellular uptake. Fluorescent probes that cannot enter cells were equipped with cyclic disulfides of gradually increasing ring tension. As demonstrated by flow cytometry experiments, uptake into HeLa Kyoto cells increased with increasing tension. Differences in carbon-sulfur-sulfur-carbon (CSSC) dihedral angles as small as 88 caused significant changes in uptake efficiency. Uptake with high ring tension was better than with inactivated or activated linear disulfides or with thiols. Conversion of thiols on the cell surface into sulfides and disulfides decreased the uptake. Reduction of exofacial disulfides into thiols increased the uptake of transporters with disulfides and inactivated controls with thiols. These results confirm the occurrence of dynamic covalent disulfide-exchange chemistry on cell surfaces. Mechanistic and colocalization studies indicate that endocytosis does not fully account for this cellular uptake with ring tension.
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