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Updated: Jun 25, 2026

Site-Specific Lysine Lactylation via Genetic Code Expansion in E. coli and Mammalian Cells
Published on: February 24, 2026
Post-Translational Aldehyde-Mediated Backbone Alkylation Enables Constrained α-Amino-γ-Lactam Motifs in mRNA Display
1Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan.
Abstract:
Display technologies discover high-affinity peptides from vast combinatorial libraries. In mRNA display, flexizyme-enabled genetic code reprogramming has become the dominant approach to extend building block diversity and improve drug-relevant properties, yet post-translational modifications (PTMs) capable of installing more uniquely constrained backbone topologies remain underexplored. Here, we introduce a PTM strategy that broadens this scope by installing an aspartyl aldehyde (X), which undergoes spontaneous Pictet-Spengler-type cyclization with proximal nucleophilic side chains to yield polycyclic α-amino-γ-lactam (pcAgl) motifs. Systematic studies define the equilibria, stereochemistry, and side-chain requirements governing pcAgl formation under biocompatible conditions. Incorporation of this chemistry into reprogrammed peptide libraries enabled direct in vitro selection of pcAgl-containing ligands against the oncology target MAT2A. The selected peptides contained structurally critical pcAgl motifs, inhibited the enzyme (best IC50 = 9 μM), and showed improved stability in human serum. This work establishes aldehyde-mediated peptide backbone alkylation in mRNA display and showcases the value of applying chemistries traditionally not considered biocompatible to expand the chemical space of genetically encoded libraries.
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