Discovery of De Novo Macrocyclic Peptides by Messenger RNA Display. (May 2021)

• Record Type: Journal Article
• Authors: Peacock, Hayden; Suga, Hiroaki
• Is Part Of: Trends in pharmacological sciences. Volume 42:Number 5(2021)
• Page Start: 385
• Page End: 397
• Publication Date: 2021-05
• Subjects: macrocyclic peptides -- in vitro translation -- drug discovery -- protein–protein interactions; Pharmacology -- Periodicals; Pharmacology -- trends -- Periodicals; Pharmacologie -- Périodiques; Pharmacology; Electronic journals; Periodicals; 615.1
• DOI: 10.1016/j.tips.2021.02.004
• Languages: English
• ISSNs: 0165-6147

Abstract

Abstract : Macrocyclic peptides are a promising class of compounds that can often engage challenging therapeutic targets. Display technologies, such as mRNA display, allow for the efficient discovery of macrocyclic peptides. This article reviews the current approaches for generating macrocyclic peptide libraries using mRNA display and highlights some recent examples of ribosomal incorporation of nonproteinogenic amino acids into macrocyclic peptides. Highlights: Macrocyclic peptides are able to bind to therapeutic targets with high affinity and selectivity. mRNA display is a technique that selects peptides from large libraries based on their binding affinity for a target. Various cyclization strategies permit the generation of macrocyclic peptide libraries on mRNA display. The installation of nonproteinogenic amino acids confers favorable properties on peptides. Until recently, the ribosomal incorporation of consecutive d - and β-amino acids into peptides has not been possible. This has been overcome with engineered tRNAs. Large and non-natural structures can be incorporated into peptides by ribosomal synthesis.