Minireview details on-resin late-stage functionalization methods for peptide drug development

Peptides hold a unique position in drug discovery, offering high target specificity and favorable safety profiles, yet their widespread application is often hampered by intrinsic conformational flexibility and suboptimal drug-like properties. Chemical modification is crucial for tailoring peptide structure and function to overcome these limitations, particularly in peptide drug development. Current methods for incorporating non-canonical residues can be complex or inefficient. There is a high demand for straightforward, cost- and time-efficient modification techniques that can streamline the development of novel peptide therapeutics.

This minireview comprehensively surveys chemical approaches for on-resin late-stage peptide functionalization, focusing on developments over the past decade. The authors categorized and discussed various reaction types, ranging from nucleophilic substitution and carbonyl chemistry to metal catalysis and photocatalysis. The review assessed the compatibility of these methods with both short and long peptides, and their demonstrated ability to modulate peptide bioactivity. The overarching goal was to highlight tools that enable high-throughput experimentation, thereby accelerating the discovery and optimization of peptide therapeutics.

The review highlights a diverse array of chemical approaches for on-resin late-stage peptide functionalization, emphasizing their utility in tailoring peptide properties. These methods include nucleophilic substitution, carbonyl chemistry, metal catalysis, and photocatalysis, all of which have seen significant development over the past decade. Many of the presented approaches have been shown to be compatible with both short and long peptides, demonstrating broad applicability across various peptide scaffolds. > These functionalization techniques effectively modulate peptide bioactivity and enable high-throughput synthesis of peptide libraries, significantly streamlining the development of peptide therapeutics. The authors underscore that on-resin late-stage functionalization is a powerful, cost- and time-efficient tool, facilitating rapid exploration of chemical space. Impressive examples of peptide library synthesis in high-throughput formats illustrate the substantial potential of these methods for future advancements in peptide drug development.