康 · 学术 | Reaction of the Day No. 1712

来源：市场资讯

（来源：康龙化成）

Desulfurative Modification of Cysteine Residues in Peptides andProteins via the Installation and Photoexcitation of Thieno[2,3-c]-pyrroles

Zijing Chen, Wenjun Wang, Baicheng Chen, Si-Cong Chen, AimilaAoken, Fanrui Wu, Guihua Zeng and Tuoping Luo

a. Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Beijing National Laboratory for Molecular Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.; b. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong 999077, China.; c. Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, China.; d. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China

—Chem. Sci., 2025, doi:10.1039/d5sc05199a

Recommended by Zijing Chen_ PDM

KEY WORDS: photo chemistry, peptide modification, desulfurization (反应类型), C(sp3)–C(sp3),C(sp3)–C(sp2),C(sp3)–H (成键类型), cysteine peptides, [1.1.1]propellane, 2-cyanoindole (原料), thieno[2,3-c]-pyrroles, bioisosteres (其他)

ABSTRACT: Late-stage modification of peptides and post-translational modifications of proteins are of significant value in research, drug discovery and therapeutic development. We report the discovery of novel photoactivity in the thieno[2,3-c]-pyrrole chromophore, which enables the desulfurization of Cys residues to generate l-alanyl radicals. This approach allowed for the efficient incorporation of Trp, Tyr and Phe bioisosteres into peptides at the Cys position. Furthermore, we developed a new reagent to install the photoreactive thieno[2,3-c]-pyrrole on the Cys residues in a biocompatible manner, enabling photodesulfurization in both cell lysates and live cells.

Desulfurative transformations of cysteine on model substrates. (A) Photoreaction of the model thieno[2,3-c]-pyrrole. (B) One-pot transformation of cysteine to 2-cyanotryptophan on a model peptide (VTCG). (C) Optimization of the reaction conditions. (D) Other radical-trapping products derived from VTCG

One-pot desulfurative transformations on catalog peptides. a[1.1.1]propellane, B2(cat)2, then H2O2. dDMPO. e2-cyanoindole. f[1.1.1]propellane, B2(cat)2

Electrophilic Cys arylation with thieno[2,3-c]-pyrrole 4-sulfonate and 6-sulfonate. (A) Isomerization and deuteriation in D2O at rt. (B) Installation of thieno[2,3-c]-pyrroles through sodium sulfonate reagents and the subsequent photoreaction

Summary and Comments

In conclusion, Zijing Chen et al. have developed a novel approach for site-specific cysteine modification and desulfurization in peptides and proteins, leveraging thieno[2,3-c]-pyrrole-based reagents and photochemical activation. The method doesn't require the use of a phosphine that disrupts disulfide bonds and strong electrophilic reagents, making it applicable for the selective targeting of free Cys residues under mild conditions. The application of this strategy was demonstrated in both cell lysates and live mammalian cells, with successful labeling and desulfurization of proteins. Additionally, this method enabled the introduction of bioisosteric amino acid analogs.

北京大学的Zijing Chen等人开发了一种新颖的多肽/蛋白质中半胱氨酸脱硫转化方法。该方法利用噻吩[2,3-c]-吡咯衍生物的光化学性质，实现了天然氨基酸残基类似物（或其生物电子等排体）在原半胱氨酸位点的后期引入。该方法避免了膦类及强亲电试剂的使用，条件温和。能够在不破坏二硫键的情况下，选择性地修饰游离态半胱氨酸。该反应底物适用范围广，能兼容其它天然残基，并在水相为主的反应介质中，以一锅法直接实现多种类型的转化。