(Poly)Borylated Species as Modern Reactive Groups toward Unusual Synthetic Applications

In this review, we spotlight recent breakthroughs in α-polyboron-substituted carbon-centered intermediates (carbanion, carbocation, radical, and carbene) and polyborylated alkenes. By bridging fundam...

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Advancing protein engineering via organic chemistry

Communications Chemistry, Published online: 18 April 2026; doi:10.1038/s42004-026-02033-3Selective protein functionalization remains difficult to achieve through conventional molecular biology approaches. Here, the authors summarize recent advances in chemical approaches to protein engineering and highlight their emerging applications in catalysis, functional studies, and therapeutic development.

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Biocompatible organometallics for in-cell protein arylation - Nature Chemistry

Transition-metal chemistry has transformed modern organic synthesis, enabling the generation of novel compounds in vitro. Now, biocompatible organometallic reagents have been shown to enable selective...

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Engineering Light-Responsive Transcription Factors via Strategic Masking of Post-translational Modification Residues

The development of synthetic transcription factors (TFs) that generate functional outputs in response to specific stimuli holds significant promise for modulating key cellular processes in both basic ...

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Biocompatible ligand balancing in transition metal coordination enables benign in-cell protein arylation - Nature Chemistry

The perceived toxicity of organometallic reagents has limited their use in living systems. Now it has been shown that balancing flexible chelation with biocompatible ligands without precluding chemica...

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Chemical Engineering of Transcription Factors Uncovered Cell-Permeable μMax Modulators

Transcription factor engineering has emerged as a powerful strategy for generating novel proteins for fundamental research and biomedical applications. Although various analogs have been developed, th...

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One-Pot Total Synthesis of a Post-translationally Modified Max Transcription Factor Sheds Light on Ser-Phosphorylation and Lys-Acetylation Crosstalk in DNA Binding

We report a one-pot total synthesis of the transcription factor Max in seven consecutive steps, starting from three peptide segments and employing native chemical ligation. The developed synthesis fac...

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A glycan foldamer that uses carbohydrate–aromatic interactions to perform catalysis - Nature Chemistry

In nature, catalysis is generally performed by proteins and ribozymes. Now it has been shown that glycans can be designed to perform catalysis. Exploiting carbohydrate–aromatic interactions, a glycan ...

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Optimized Directed Evolution of E. coli leucyl‐tRNA Synthetase adds many Noncanonical Amino Acids into the Eukaryotic Genetic Code Including Ornithine and Nϵ‐Acetyl‐Methyllysine

The pyrrolysyl pair has dominated noncanonical amino acids (ncAAs) incorporation in eukaryotes, but additional engineerable pairs are needed to further expand this toolbox. Although E. coli leucyl-tR....

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Late-Stage Minimal Labeling of Peptides and Proteins for Real-Time Imaging of Cellular Trafficking

The cellular uptake routes of peptides and proteins are complex and diverse, often handicapping therapeutic success. Understanding their mechanisms of internalization requires chemical derivatization with approaches that are compatible with wash-free and real-time imaging. In this work, we developed a new late-stage labeling strategy for unprotected peptides and proteins, which retains their biological activity while enabling live-cell imaging of uptake and intracellular trafficking. Benzo-2,1,3-thiadiazoles were selectively incorporated into Cys residues of both linear and cyclic peptides via Pd-mediated arylation with good yields and high purities. The resulting labeled peptides are chemically stable under physiological conditions and display strong fluorogenic character for wash-free imaging studies. We utilized this approach to prepare native-like analogues of cell-penetrating peptides and performed time-course analysis of their internalization routes in live cells by fluorescence lifetime imaging. Furthermore, we applied our strategy to label the chemokine protein mCCL2 and monitor its internalization via receptor-mediated endocytosis in live macrophages. This study provides a straightforward strategy for late-stage fluorogenic labeling of intact peptides and small proteins and direct visualization of dynamic intracellular events.

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