Ribosomal synthesis of unnatural peptides.
Ribosomal Synthesis of N-Methyl Peptides J.
Another approach to generate genetically encoded nonstandard peptide libraries involves the engineering of a ribosomal translation system, that is, cotranslational incorporation of nonproteinogenic amino acids into ribosomally synthesized polypeptides (). This approach is further divided into two strategies: genetic code expansion and genetic code reprogramming. In this paper, we discuss both strategies and their application for the generation of genetically encoded nonstandard peptide libraries as well as the use of these libraries for the selection/evolution of functional nonstandard peptides.
"Ribosomal Synthesis of N-methylated peptides" by Sara …
Nonstandard peptides, also known as unnatural peptides or peptidomimetics, are peptide-based small molecules containing a moiety that does not exist in standard (i.e., natural) peptides composed of only 20 proteinogenic amino acids. The nonproteinogenic moiety in nonstandard peptides, such as a nonproteinogenic side chain, a modified backbone, or a macrocyclized backbone, often contributes to improving the peptide's cell permeability, stability against peptidases, and conformational rigidity, thereby affording specific high affinity toward its target molecule [–]. Naturally occurring nonribosomal peptides (e.g., immunosuppressant cyclosporine A) are representative of nonstandard peptides, and given the success of nonribosomal peptides as therapeutics, the development of methods to construct highly diverse drug-like nonstandard peptide libraries is important for the discovery of novel drug candidates. Chemical synthesis can generate highly modified drug-like nonstandard peptide libraries, but the size of these libraries is relatively small (with a diversity of up to 106 unique compounds). In contrast, by using genotype-phenotype linking technology, ribosomal synthesis can generate genetically encoded peptide libraries with extremely high diversity (up to 1013 compounds) [–]. However, ribosomally synthesized peptide libraries are typically composed of just the 20 proteinogenic amino acids. This had led to the development of various strategies to generate highly diverse nonstandard peptide libraries; these strategies integrate biology-based methods to construct highly diverse libraries and chemistry-based methods to construct highly modified drug-like libraries.