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Proteolysis-Assisted Cyclization Facilitates Site-Centric Target Deconvolution of Isothiocyanates
Jingyang He1,2, Caiping Tian2, Qiang Li3
1School of Basic Medical Sciences, Tsinghua University, Beijing, China.
Angewandte Chemie (International Ed. in English)
|May 12, 2026
Summary
Isothiocyanates (ITCs) react with proteins, but identifying targets is hard. A new method, proteolysis-assisted cyclization (PAC), creates stable adducts for profiling ITC targets and discovering new drug targets.
Area of Science:
- Natural product chemistry
- Chemical biology
- Proteomics
Background:
- Isothiocyanates (ITCs) are electrophilic natural products known for their biological effects.
- ITCs react with protein cysteines, forming labile thionoacyl adducts.
- Identifying specific ITC target sites has been challenging due to adduct instability.
Purpose of the Study:
- To develop novel chemoproteomic methods for site-specific profiling of ITC targets.
- To overcome the challenge of labile adducts in identifying ITC-protein interactions.
- To expand the understanding of ITC polypharmacology and cysteine targetability.
Main Methods:
- Discovery of an unexpected proteolysis-assisted cyclization (PAC) reaction.
- Development of affinity-based and activity-based chemoproteomic assays utilizing PAC.
- Application of a 55-member ITC library to profile targets.
Main Results:
- ITC-protein adducts form stable N-terminal dihydrothiazole peptide adducts during proteolysis via PAC.
- The PAC method enabled site-specific profiling of ITC targets.
- The study expanded the known ligandable cysteinome with high resolution.
Conclusions:
- The PAC reaction provides a stable adduct for identifying ITC targets.
- PAC-based chemoproteomics offers a powerful platform for elucidating ITC mechanisms of action.
- This approach can diversify cysteine targetability for drug discovery.
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