mRNA display: from basic principles to macrocycle drug discovery

• Novel approaches are needed to tackle undruggable targets.
• Larger macrocycles are an underexplored region of drug space.
• mRNA-display has been adapted for the discovery of novel macrocyclic peptides.
• Early examples of these compounds are potent and highly selective.
• Approaches and strategies for improving this technology are discussed.

We describe a new discovery technology that uses mRNA-display to rapidly synthesize and screen macrocyclic peptide libraries to explore a valuable region of chemical space typified by natural products. This technology allows high-affinity peptidic macrocycles containing modified backbones and unnatural side chains to be readily selected based on target binding. Success stories covering the first examples of these libraries suggest that they could be used for the discovery of intracellular protein–protein interaction inhibitors, highly selective enzyme inhibitors or synthetic replacements for monoclonal antibodies. The review concludes with a look to the future regarding how this technology might be improved with respect to library design for cell permeability and bioavailability.