Bioconjugate Platform for Iterative Backbone N-Methylation of Peptides

Yiwu Zheng, Chayanid Ongpipattanakul, Satish K. Nair

Research output: Contribution to journalArticlepeer-review

Abstract

N-methylation of peptide backbones has often been utilized as a strategy toward the development of peptidic drugs. However, difficulties in the chemical synthesis, high cost of enantiopure N-methyl building blocks, and subsequent coupling inefficiencies have hampered larger-scale medicinal chemical efforts. Here, we present a chemoenzymatic strategy for backbone N-methylation by the bioconjugation of peptides of interest to the catalytic scaffold of a borosin-type methyltransferase. Crystal structures of a substrate tolerant enzyme from Mycena rosella guided the design of a decoupled catalytic scaffold that can be linked via a heterobifunctional cross-linker to any peptide substrate of choice. Peptides linked to the scaffold, including those with nonproteinogenic residues, show robust backbone N-methylation. Various cross-linking strategies were tested to facilitate substrate disassembly, which enabled a reversible bioconjugation approach that efficiently released modified peptides. Our results provide general framework for the backbone N-methylation on any peptide of interest and may facilitate the production of large libraries of N-methylated peptides.

Original languageEnglish (US)
Pages (from-to)14006-14014
Number of pages9
JournalACS Catalysis
Volume12
Issue number22
DOIs
StatePublished - Nov 18 2022

Keywords

  • RiPP
  • backbone N-methylation
  • bioconjugation
  • enzyme
  • peptide

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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