Cyclic Thiosulfinates and Cyclic Disulfides Selectively Cross-Link Thiols While Avoiding Modification of Lone Thiols

Area of Science:

• Chemical Biology
• Organic Chemistry
• Biochemistry

Background:

• Contemporary thiol-selective cross-linkers often result in toxic "dead-end" modifications.
• These undesired byproducts complicate macromolecular structure studies and polymer synthesis.

Purpose of the Study:

• To develop novel chemical tools for selective thiol cross-linking.
• To overcome limitations of existing cross-linking agents by minimizing dead-end modifications.

Main Methods:

• Utilized the thiol pair of copper/zinc-superoxide dismutase (SOD1) for testing.
• Employed density functional theory (DFT) calculations to understand reaction mechanisms.
• Synthesized five- to seven-membered cyclic thiosulfinates.

Main Results:

• Cyclic disulfides, like lipoic acid, showed efficient thiol pair cross-linking without dead-end products.
• Mono-S-oxo derivatives (cyclic thiosulfinates) accelerated cross-linking up to 10^4-fold compared to cyclic disulfides.
• The new thiosulfinate cross-linkers demonstrated cell permeability, potency, and functionality in the presence of glutathione.

Conclusions:

• Cyclic thiosulfinates represent a new class of highly efficient, selective thiol cross-linkers.
• These compounds exhibit click-like attributes, including high yields, orthogonality, and water-compatibility.
• The developed cross-linkers are suitable for intracellular applications and advanced polymer synthesis.