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<p>Protein and polypeptide heteropolymers containing non-α-backbone monomers are highly desirable as potential materials and therapeutics but many remain difficult or impossible to biosynthesize in cells using traditional genetic code expansion. Here we describe a next-generation approach to such materials that relies instead on proximity-guided intramolecular rearrangements that edit the protein backbone post-translationally. This approach relies on orthogonal aminoacyl-tRNA synthetase enzymes that accept α-hydroxy acid monomers whose side chains contain masked nucleophiles. Introduction of such an α-hydroxy acid into a protein translated in vivo, followed by nucleophile unmasking, sets up a thermodynamically favored intramolecular backbone extension acyl rearrangement (BEAR) reaction that edits the protein to install an extended-backbone monomer. In the examples described here, BEAR reactions are used to generate protein heteropolymers containing a β-backbone, γ-backbone or δ-backbone. This report represents a general strategy to install extended backbones into genetically encoded proteins and peptides expressed in cells.</p><p></p>

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Site-selective protein editing by backbone extension acyl rearrangements

  • 期刊论文

  • 发表日期：

    2025年8月21日

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  • Leah T. Roe,
  • Isabel M. Piper,
  • Carly K. Schissel,
  • Taylor L. Dover,
  • Bhavana Shah,
  • Noah X. Hamlish,
  • Arjun M. Garapaty,
  • Shuai Zheng,
  • Diondra A. Dilworth,
  • Nicole Wong,
  • Zhongqi Zhang,
  • Abhishek Chatterjee,
  • Matthew B. Francis,
  • Scott J. Miller,
  • Alanna Schepartz

摘要

Protein and polypeptide heteropolymers containing non-α-backbone monomers are highly desirable as potential materials and therapeutics but many remain difficult or impossible to biosynthesize in cells using traditional genetic code expansion. Here we describe a next-generation approach to such materials that relies instead on proximity-guided intramolecular rearrangements that edit the protein backbone post-translationally. This approach relies on orthogonal aminoacyl-tRNA synthetase enzymes that accept α-hydroxy acid monomers whose side chains contain masked nucleophiles. Introduction of such an α-hydroxy acid into a protein translated in vivo, followed by nucleophile unmasking, sets up a thermodynamically favored intramolecular backbone extension acyl rearrangement (BEAR) reaction that edits the protein to install an extended-backbone monomer. In the examples described here, BEAR reactions are used to generate protein heteropolymers containing a β-backbone, γ-backbone or δ-backbone. This report represents a general strategy to install extended backbones into genetically encoded proteins and peptides expressed in cells.