Peptide Backbone Editing via Post-Translational O to C Acyl Shift

Area of Science:

• Chemical Biology
• Synthetic Chemistry
• Biochemistry

Background:

• Ribosomes synthesize peptides using only amide, ester, and thioester bonds.
• Forming backbone-embedded C-C bonds in peptides is a significant challenge in synthetic biology.
• Existing methods lack strategies for site-selective C-C bond formation within peptide backbones.

Purpose of the Study:

• To develop a novel nonenzymatic strategy for peptide backbone editing.
• To enable the formation of C-C bonds within peptide backbones.
• To create diverse protein-like materials with backbone-embedded heterocycles.

Main Methods:

• Introduction of a dehydrolactic acid motif into peptides via ribosomal or solid-phase synthesis.
• Oxidation of α-hydroxyphenylselenocysteine to introduce the motif.
• Spontaneous isomerization and acyl shift rearrangement at physiological pH.

Main Results:

• Peptides with a dehydrolactic acid motif isomerize to form backbone-embedded α,γ-diketoamides.
• The α,γ-diketoamide products can be diversified using nucleophiles like hydrazines and hydroxylamines.
• This process yields pyrazoles and oximes embedded within the polypeptide backbone.

Conclusions:

• A novel nonenzymatic peptide backbone editing strategy is established.
• This method provides the first example of C-C bond formation within a peptide backbone.
• The strategy accelerates the discovery of genetically encoded molecules resembling bioactive natural products.