Synthetic Mutagenesis of Tyrosine into Proline Mimetics Enables Late-Stage Backbone Editing of Peptides
4 affiliations
- 1Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113-0033
- 2Graduate School of Pharmaceutical Sciences, The University of Osaka, 1-6 Yamadaoka, Suita, Osaka, Japan, 565-0871
- 3Open Innovation Laboratory for Food and Medicinal Resource Engineering (FoodMed-OIL), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan, 305-8577
- 4Catalytic Chemistry Research Institute (CCRI), National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5-2, 1-1-1 Higashi, Tsukuba, Ibaraki, Japan, 305-8565
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.
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BibTeX
@misc{togo2026synthetic,
title = {{Synthetic Mutagenesis of Tyrosine into Proline Mimetics Enables Late-Stage Backbone Editing of Peptides}},
author = {Takaya Togo and Takumi Ueda and Yuko Otani and Yuka Furukawa and Kohei Nogita and Katsuya Maruyama and Koh Takeuchi and Motomu Kanai and Kounosuke Oisaki},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008909/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008909/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Synthetic Mutagenesis of Tyrosine into Proline Mimetics Enables Late-Stage Backbone Editing of Peptides
AU - Takaya Togo
AU - Takumi Ueda
AU - Yuko Otani
AU - Yuka Furukawa
AU - Kohei Nogita
AU - Katsuya Maruyama
AU - Koh Takeuchi
AU - Motomu Kanai
AU - Kounosuke Oisaki
PY - 2026
DA - 2026/09/16
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008909/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008909/v1
AB - 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.
ER -