Cysteine-Specific Bioconjugation and Stapling of Unprotected Peptides by Chlorooximes

Cyclic peptides have found applications in fields ranging from drug discovery to nanomaterials. Peptide stapling reagents crosslink two or more residues in peptides to generate macrocycles of diverse topology and introduce linker units that might directly impact the properties and biological functions of cyclic peptides. Herein, we demonstrate that chlorooxime derivatives are cysteine-specific peptide bioconjugation and stapling reagents that generate stable thiohydroximate linkages. In addition, chlorooximes have multiple reaction modes with 1,2-aminothiols and alkynes by generating 4,5-dihydrothiazole and isoxazole motifs, which further expands the structural diversity of cyclic peptides. The high reactivity and chemoselectivity of chlorooximes toward cysteine might support their application in constructing a cyclic peptide library. [GRAPHICS] .

Automated summary

Chlorooxime derivatives are cysteine-specific peptide bioconjugation and stapling reagents that can generate stable thiohydroximate linkages, expanding the structural diversity of cyclic peptides.