• disulfides;
  • drug delivery;
  • electrostatic interactions;
  • linkers;
  • peptides


The interplay between the chemical microenvironment surrounding disulfides and the redox environment of the media on thiol–disulfide exchange kinetics was examined by using a peptide platform. Exchange kinetics of up to 34 cysteine-containing peptides were measured in several redox buffers. The electrostatic attraction/repulsion between charged peptides and reducing agents such as glutathione was found to have a very pronounced effect on thiol–disulfide exchange kinetics (differences of ca. three orders of magnitude). Exchange kinetics could be directly correlated to peptide charge over the entire range examined. This study highlights the possibility of finely and predictably tuning thiol–disulfide exchange, and demonstrates the importance of considering both the local environment surrounding the disulfide and the nature of the major reducing species present in the environment for which their use is intended (e.g., in drug delivery systems, sensors, etc).