Ribosomal Synthesis of Macrocyclic Peptides with Linear γ4- and β-Hydroxy-γ4-amino Acids.

Herein, we report the ribosomal elongation of linear γ4- and β-hydroxy-γ4-amino acids (statines) to expand the nonproteinogenic amino acid repertoire of natural product-like combinatorial peptide libraries. First, we demonstrated the successful ribosomal incorporation of four linear γ4-amino acids (γ4Gly, (S)-γ4Ala, (S)-γ4Nva, and (R)-γ4Leu) into a 10-mer macrocyclic peptide scaffold. Given the promising effects reported for statines on the cell permeability of macrocyclic peptides, we also designed and tested the ribosomal incorporation of six statines derived from Ala and d-val. Four Ala-derived statines were successfully incorporated into peptides, and γ4SAla3R-OH (GP2) showed a similar efficiency of incorporation to that of (S)-β2hAla and l-Ala. These new building blocks might confer the important pharmacological properties of protease resistance and membrane permeability to macrocyclic peptides and expand the diversity of future combinatorial peptide libraries that can be translated by the ribosome.