mRNA Display and Its Growing Potential in the Discovery of De Novo Therapeutic Peptide Candidates

As an in vitro directed evolution technology, mRNA display is highly versatile, and allows screening of combinatorial libraries containing trillions of peptides. The adaptability of this screening platform has inspired rapid technological advances within the last two decades, most notably being the development of the ‘flexizyme’, which facilitates genetic code reprogramming and the incorporation of non-proteogenic amino acids. The incorporation of N-alkylated amino acids, d-amino acids and macrocyclization has shifted lead discovery towards more natural product-like ligands with improved pharmacokinetic properties. mRNA display has been particularly successful at identifying high-affinity binders for well-behaved protein targets in vitro, but the technology is still challenged by a lack of general solutions for selecting desired functions and identifying more drug-like macrocyclic peptides. In this article, we review the development of mRNA peptide display, its application in drug discovery, challenges and future outlook.