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 language | English (US) |
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Pages (from-to) | 14006-14014 |
Number of pages | 9 |
Journal | ACS Catalysis |
Volume | 12 |
Issue number | 22 |
DOIs | |
State | Published - Nov 18 2022 |
Keywords
- RiPP
- backbone N-methylation
- bioconjugation
- enzyme
- peptide
ASJC Scopus subject areas
- Catalysis
- General Chemistry