Extraordinary Modulation of Disulfide Redox‐Responsiveness by Cooperativity of Twin‐Disulfide Bonds

Abstract

Disulfide bonds have frequently been incorporated into synthetic materials to promote sensitivity of the systems towards different redox environments. Although many strategies have been developed to rationally tune the stability of disulfide linkers, methods to tune their responsiveness towards different redox environments remain elusive. In this work we have developed and explored a disulfide linker bearing two independent disulfide bonds, referred to as a twin-disulfide linker. We have demonstrated that the twin-disulfide linker displays an ultrahigh stability at lower concentrations of reducing agent or in weakly reducing environments without a significant compromise in the sensitivity of its response to highly reducing environments such as cytoplasm, a feature that is in remarkable contrast to the traditional single disulfide bonds. Such an extraordinary responsiveness arises from the cooperativity of the twin-disulfide bonds, which should be of particular interest for applications such as controlled drug delivery and sensing, because relatively large differences in disulfide stability in different redox environments is desired in these applications.

Disulfide-Linked/Peptide-Incorporated Macrocycles: Unique Redox-Responsiveness and Application for Intracellular Cargo-Delivery

“…This is also supported by the reported result that the reduction of the C‐NDI−C dimer by GSH (10–20 equiv.) cannot compete against the intramolecular disulfide isomerizations, because local concentration of thiols present in the partially reduced intermediates is much higher than the GSH concentration in solution. More detailed studies on the mechanism were given in the Supporting Information, and the proposed mechanism was demonstrated to be applicable to other peptide dithiols, including, CGC‐, CRC‐, and CGGGC‐containing peptides (See the Supporting Information).…”

“…The isomerization of I 1 leads to the formation of the closed‐loop peptide and C‐NDI‐C GSH . In contrast, thiol‐disulfide exchanges within the I 2 tend to form either the original CGGC/C‐NDI−C or the I 1 , because disulfide formation within C‐NDI−C is impossible . This deduction is in agreement with the result that the closed‐loop peptide and C‐NDI‐C GSH are both the major products observed.…”

“…Despite extensive progress in this field and the presence of multiple disulfides within the macrocycles, the response of the macrocycles to redox‐stimulation has not been systematically studied . Furthermore, the utility of the disulfide‐linked macrocycles for the development of delivery systems for drugs or imaging agents is also unexplored, though disulfide‐linked macrocycles are expected to exhibit unique redox‐responsiveness , . This is, at least partially, due to the lack of a straightforward strategy to incorporate a cell‐surface binding unit into the macrocycles to facilitate cellular uptake.…”

“…However, the trimeric macrocycle was significantly more stable than its non‐cyclic analogue in weakly reducing buffers containing a lower concentration of GSH (0.2–1 mM, Figure ). To further quantitatively compare their redox‐responsiveness, half‐lives of disappearance (τ 1/2 ) of the trimeric macrocycle and its non‐cyclic analogue were extracted by nonlinear‐fittings of the cleavage kinetic curves . As seen in Figure c, where the plots of τ 1/2 as a function of the inverse concentration of GSH ([GSH] –1 ) was shown, the non‐cyclic trimer displays a linear τ 1/2 –[GSH] –1 correlation (pseudo‐first‐order rate equation); however, there is a clear deviation from linear trend for the trimeric macrocycle.…”

A Ratiometric Near‐Infrared Fluorescent Probe for Quantification and Evaluation of Selenocysteine‐Protective Effects in Acute Inflammation

“…Cys‐SSH whose p K a was ≈4.34 could not cause the interference. The slow reaction rates for exchange reactions are attributed to the kinetic and thermodynamic properties of biothiols with their disulfide‐containing compounds . For the selective detection of Sec in cells, the interferences from SePs, such as GPx and Trx, must be eliminated .…”