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In animal cells, the extracellular matrix allows cells within tissues to withstand external stresses and transmits signals from the outside of the cell to the inside. The extracellular matrix is extensive, and its composition varies between different types of tissues. For example, the reticular fibers and ground substance make up the ECM in loose connective tissue, while collagen and bone minerals make up the ECM of bone tissue. 
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Updated: Apr 13, 2026

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Ring Tension Applied to Thiol-Mediated Cellular Uptake.

Giulio Gasparini1, Gevorg Sargsyan1, Eun-Kyoung Bang1,2

  • 1School of Chemistry and Biochemistry, NCCR Chemical Biology, University of Geneva, Geneva (Switzerland) http://www.unige.ch/sciences/chiorg/matile/

Angewandte Chemie (International Ed. in English)
|May 1, 2015
PubMed
Summary
This summary is machine-generated.

Ring tension in cyclic disulfides enhances cellular uptake. This study demonstrates that increasing disulfide ring strain improves thiol-mediated cell entry, revealing dynamic covalent chemistry on cell surfaces.

Keywords:
cell-penetrating peptidescellular uptakedihedral anglesdisulfidesring tension

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Chemical Biology

Background:

  • Cellular uptake mechanisms are crucial for drug delivery and biological processes.
  • Disulfide bonds play vital roles in protein structure and cellular redox homeostasis.
  • Understanding how molecular structure influences cell entry is key to developing targeted therapies.

Purpose of the Study:

  • To investigate the role of ring tension in cyclic disulfides for promoting thiol-mediated cellular uptake.
  • To quantify the impact of varying disulfide ring strain on cellular entry efficiency.
  • To elucidate the underlying chemical mechanisms of disulfide-mediated cell penetration.

Main Methods:

  • Synthesis of fluorescent probes functionalized with cyclic disulfides of incrementally increasing ring tension.
  • Flow cytometry to measure cellular uptake of probes in HeLa Kyoto cells.
  • Analysis of carbon-sulfur-sulfur-carbon (CSSC) dihedral angles and their correlation with uptake.
  • Cell surface thiol modification (sulfidation, disulfide formation) and reduction experiments.
  • Mechanistic and colocalization studies to assess uptake pathways.

Main Results:

  • Cellular uptake of fluorescent probes increased significantly with escalating cyclic disulfide ring tension.
  • Even minor variations in CSSC dihedral angles (as small as 8°) markedly affected uptake efficiency.
  • High ring tension disulfides demonstrated superior uptake compared to linear disulfides or free thiols.
  • Modifying cell surface thiols or reducing external disulfides altered probe uptake, confirming dynamic disulfide exchange.
  • Endocytosis was found to be insufficient to explain the observed uptake driven by ring tension.

Conclusions:

  • Ring tension in cyclic disulfides is a critical determinant for efficient thiol-mediated cellular uptake.
  • Dynamic covalent disulfide-exchange chemistry actively occurs on cell surfaces, influencing molecular entry.
  • This finding opens new avenues for designing cell-penetrating molecules by exploiting disulfide bond strain.