Synthetic Mutagenesis of Tyrosine into Proline Mimetics Enables Late-Stage Backbone Editing of Peptides
Year: 2026
Type: preprint
Abstract: The biological and physicochemical properties of peptides are strongly influenced by their backbone conformations. However, installing conformationally restricting units generally requires peptide redesign and resynthesis using noncanonical amino acids. Here, we report a late-stage backbone-editing method that converts a native amino acid residue into a proline-mimetic structure. Treatment of the dearomatized intermediate generated by tyrosine-selective oxime conjugation in a basic aqueous buffer induced intramolecular 1,4-addition of the backbone amide nitrogen, thereby converting the tyrosine residue into a cyclic proline-mimetic unit within the peptide backbone. This transformation proceeded efficiently under mild aqueous conditions and was applicable to several bioactive peptides. Multidimensional NMR analyses established the structures of the resulting products, while conventional molecular dynamics and REST2 simulations demonstrated that the installed proline-mimetic backbone reduced the local conformational freedom of the peptide. Evaluation using a β-hairpin model peptide further demonstrated that the proline-mimetic structure enhanced resistance to proteolytic degradation. This method constitutes a chemical mutagenesis strategy that directly converts a native tyrosine residue into a backbone conformational control unit without reconstructing the parent peptide sequence. By connecting residue-selective side-chain modification with backbone editing, this strategy provides a new design concept for the late-stage conformational and functional diversification of peptides.
Source: ChemRxiv
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7213400029