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Updated: Jun 25, 2026
05:58
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.
Journal of the American Chemical Society
|June 24, 2026
Summary
We developed a new method using mRNA display to create novel peptides with constrained backbones. This approach enables the discovery of drug-like molecules with enhanced stability and therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- mRNA display is a powerful technique for discovering high-affinity peptides.
- Current methods using flexizyme-enabled genetic code reprogramming expand building block diversity but underexplore backbone modifications.
- Post-translational modifications (PTMs) for constrained peptide backbones are underexplored in display technologies.
Purpose of the Study:
- To introduce a novel PTM strategy for creating constrained peptide backbone topologies in mRNA display.
- To establish and characterize aldehyde-mediated peptide backbone alkylation for generating polycyclic α-amino-γ-lactam (pcAgl) motifs.
- To demonstrate the utility of this approach for in vitro selection of functional peptide ligands.
Main Methods:
- Installation of an aspartyl aldehyde (X) PTM in mRNA display libraries.
- Pictet-Spengler-type cyclization to form pcAgl motifs under biocompatible conditions.
- Systematic studies to define reaction equilibria, stereochemistry, and side-chain requirements.
- In vitro selection of pcAgl-containing peptides against the oncology target MAT2A.
Main Results:
- Successfully generated pcAgl motifs via spontaneous cyclization of aspartyl aldehyde.
- Defined conditions governing pcAgl formation, including stereochemical outcomes.
- Selected pcAgl-containing peptides that inhibit MAT2A with an IC50 of 9 μM.
- Demonstrated improved serum stability of selected peptides.
Conclusions:
- Aldehyde-mediated peptide backbone alkylation is a viable strategy in mRNA display.
- This PTM approach significantly expands the accessible chemical space for genetically encoded libraries.
- The developed method facilitates the discovery of novel, constrained peptides with therapeutic potential.
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