The Road Ahead for the Development of Macrocyclic Peptide Ligands

Macrocyclic peptides make up an emerging class of candidate therapeutics and chemical probes, with properties that make them potentially applicable to a wide range of targets that are intractable using current pharmacological agents. Additionally, a number of biochemical screening strategies have been developed, particularly over the past decade, that allow for the massively parallel screening of cyclic peptide libraries of up to 1 trillion compounds or more, leading to the isolation of molecules with exceptional target affinity, selectivity, and bioactivity. Clinical development of compounds derived from such screens is already underway, but the nature of these molecules means that such development is likely to follow pathways different from those of traditional small molecule drugs or well-established biologics such as monoclonal antibodies. In addition, recent work has shown that the biochemical techniques used to identify macrocyclic peptides can also be used to rapidly characterize and optimize them. These findings are likely to facilitate the development of these compounds as chemical probes and as therapeutics for areas of unmet medical need.