The presence of a nonproteinogenic moiety in a nonstandard peptide often improves the biological properties of the peptide. Non-standard peptide libraries are therefore used to obtain valuable molecules for biological, therapeutic, and diagnostic applications. Highly diverse non-standard peptide libraries can be generated by chemically or enzymatically modifying standard peptide libraries synthesized by the ribosomal machinery, using posttranslational modifications. Alternatively, strategies for encoding non-proteinogenic amino acids into the genetic code have been developed for the direct ribosomal synthesis of non-standard peptide libraries. In the strategies for genetic code expansion, non-proteinogenic amino acids are assigned to the nonsense codons or 4-base codons in order to add these amino acids to the universal genetic code. In contrast, in the strategies for genetic code reprogramming, some proteinogenic amino acids are erased from the genetic code and non-proteinogenic amino acids are reassigned to the blank codons. Here, we discuss the generation of genetically encoded non-standard peptide libraries using these strategies and also review recent applications of these libraries to the selection of functional non-standard peptides. 1. Introduction 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 [1–5]. 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) [6–9]. However, ribosomally
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