Selection-based discovery of druglike macrocyclic peptides

Annu Rev Biochem. 2014;83:727-52. doi: 10.1146/annurev-biochem-060713-035456. Epub 2014 Feb 21.


Macrocyclic peptides are an emerging class of therapeutics that can modulate protein-protein interactions. In contrast to the heavily automated high-throughput screening systems traditionally used for the identification of chemically synthesized small-molecule drugs, peptide-based macrocycles can be synthesized by ribosomal translation and identified using in vitro selection techniques, allowing for extremely rapid (hours to days) screening of compound libraries comprising more than 10(13) different species. Furthermore, chemical modification of translated peptides and engineering of the genetic code have greatly expanded the structural diversity of the available peptide libraries. In this review, we discuss the use of these technologies for the identification of bioactive macrocyclic peptides, emphasizing recent developments.

Keywords: flexizyme; genetic code expansion; genetic code reprogramming; mRNA display; phage display.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Membrane / metabolism
  • Chemistry, Pharmaceutical / methods*
  • Drug Design*
  • Genetic Code
  • High-Throughput Screening Assays
  • Peptide Library*
  • Peptides / chemistry*
  • Protein Biosynthesis
  • Protein Engineering / methods
  • Protein Interaction Mapping / methods
  • RNA, Messenger / metabolism
  • Ribosomes / chemistry


  • Peptide Library
  • Peptides
  • RNA, Messenger