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Abstract Peptide therapeutics have gained great interest due to their multiple advantages over small molecule and antibody‐based drugs. Peptide drugs are easier to synthesize, have the potential for oral bioavailability, and are large enough to target protein‐protein interactions that are undruggable by small molecules. However, two major limitations have made it difficult to develop novel peptide therapeutics not derived from natural products, including the metabolic instability of peptides and the difficulty of reaching antibody‐like potencies and specificities. Compared to linear and disulfide‐monocyclized peptides, multicyclic peptides can provide increased conformational rigidity, enhanced metabolic stability, and higher potency in inhibiting protein‐protein interactions. The identification of novel multicyclic peptide binders can be difficult, however, recent advancements in the construction of multicyclic phage libraries have greatly advanced the process of identifying novel multicyclic peptide binders for therapeutically relevant protein targets. This review will describe the current approaches used to create multicyclic peptide libraries, highlighting the novel chemistries developed and the proof‐of‐concept work done on validating these libraries against different protein targets. 

Phage display, an ingenious invention for evaluating peptide libraries, has been limited to natural peptides that are ribosomally assembled with proteinogenic amino acids. Recently, there has been growing interest in chemically modifying phage libraries to create nonnatural cyclic and multicyclic peptides, which are appealing for use as inhibitors of protein–protein interactions. While earlier reports largely focused on side-chain side-chain cyclization, we report herein a novel strategy for creating backbone-side chain cyclized peptide libraries on phage. Our strategy capitalizes on the unique reactivity of an N-terminal cysteine (NCys) with 2-cyanobenzothiazole (CBT) which, in conjugation with another thiol-reactive group, can elicit rapid cyclization between an NCys and an internal cysteine. The resulting library was screened against two model proteins, namely Keap1 and Sortase A. The screening readily revealed potent inhibitors for both proteins with certain Keap1 ligands reaching low nanomolar potency. The backbone-side chain cyclization strategy described herein presents a significant addition to the toolkit of creating nonnatural macrocyclic peptide libraries for phage display.