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

Abstract

Despite tremendous efforts to engineer translational machinery, replacing the encoded peptide backbone with new-to-nature structures remains a significant challenge. C, H, O, and N are the elements of life, yet ribosomes are capable of forming only C–N bonds as amides, C–O bonds as esters, and C–S bonds as thioesters. There is no current strategy to site-selectively form C–C bonds as ketones embedded in the backbones of ribosomal products. As an alternative to direct ribosomal C–C bond formation, here we report that peptides containing a dehydrolactic acid motif rapidly isomerize to generate backbone-embedded α,γ-diketoamides via a spontaneous formal O to C acyl shift rearrangement. The dehydrolactic acid motif can be introduced into peptides ribosomally or via solid-phase synthesis using α-hydroxyphenylselenocysteine followed by oxidation. Subsequent incubation at physiological pH produces an α,γ-diketoamide that can be diversified using a variety of nucleophiles, including hydrazines and hydroxylamines, to form pyrazoles and oximes, respectively. All of these groups remain embedded directly within the polypeptide backbone. This general strategy for peptide backbone editing, predicated on an intricate cascade of acyl rearrangements, provides the first nonenzymatic example of a C–C bond forming reaction to take place within a peptide backbone. The products so-produced are easily diversified into protein-like materials with backbone-embedded heterocycles. Application of this peptide editing strategy should accelerate the discovery of genetically encoded molecules whose properties more closely resemble those of bioactive natural products.