Article Dans Une Revue Journal of the American Chemical Society Année : 2025

Rapid C-S+ Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides

Gilles Frison
Emeric Miclet

Résumé

Peptides and proteins are invaluable therapeutics and biological tools, where stimuli-responsive and fully reversible conjugation chemistry is essential to advances in drug delivery systems and chemical biology. However, methods that allow precise conjugation, efficient regulation of biochemical functions, and customized recovery of parent peptides remain underdeveloped. Here, we introduce a straightforward yet powerful reversible chemical strategy targeting methionine (Met), a widespread yet low abundance amino acid in peptides and proteins. By selectively alkylating Met-containing peptides under weakly acidic conditions, we form a stable C–S+ bond, which can be cleaved rapidly via 1,6-benzyl elimination upon stimulus. This versatile chemistry is demonstrated in diverse applications: (i) PEGylated prodrugs of antimicrobial peptides with reduced toxicity and enhanced enzymatic stability, (ii) esterase-responsive peptide–peptide inhibitor conjugates (PPICs) with improved cell membrane permeability and therapeutic effects, (iii) reversibly stapled peptides with switchable conformations for targeting both intra- and extracellular sites, and (iv) bioorthogonal control of C-terminal Met-caged neuropeptides. Overall, this work describes, for the first time, a valuable traceless modification strategy that promises to greatly benefit the peptide community and advance the field of chemical biology.

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hal-05230446 , version 1 (29-08-2025)

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Yu Chai, Can Yu, Zhi Chen, Wenbin Duan, Huanwen Chen, et al.. Rapid C-S+ Bond Cleavage via 1,6-Benzyl Elimination for Traceless Modification of Bioactive Peptides. Journal of the American Chemical Society, 2025, 147 (24), pp.20807-20818. ⟨10.1021/jacs.5c04329⟩. ⟨hal-05230446⟩
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