Strategies for the Construction of Multicyclic Phage Display Libraries

Author:

Chen Fa‐Jie1,Pinnette Nicole2,Gao Jianmin2ORCID

Affiliation:

1. College of Chemistry Fuzhou University Fuzhou Fujian 350108 China

2. Department of Chemistry Boston College Merkert Chemistry Center 2609 Beacon Street Chestnut Hill MA-02467 USA

Abstract

AbstractPeptide 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.

Funder

National Science Foundation

National Institute of General Medical Sciences

Fuzhou University

Publisher

Wiley

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