# Making Blank Faces Expressive: Chemical Approaches to the Modification of Chemically Inert Peptides

## TL;DR

This paper reviews chemical methods to modify peptides, especially those that lack reactive groups, to create new structures efficiently.

## Contribution

The paper highlights recent advances in modifying chemically inert peptides using C–H activation and HAT chemistry.

## Key findings

- Chemical modification of existing peptides can produce functional derivatives with fewer steps than traditional synthesis.
- Recent methods target chemically inert peptides using C–H activation and HAT chemistry.
- Current techniques are limited to smaller peptides and require further development for larger ones.

## Abstract

Very minor structural modifications in peptides can result in significant changes in their function. To obtain analogues with such small structural but big functional differences compared to the original peptides, amino acid monomers are usually combined one‐by‐one from scratch, which is a simple and reliable but painfully laborious strategy. One alternative and very fascinating approach is the chemical modification of existing peptides, which allows for the rapid production of derivatives with fewer synthetic steps. However, such approaches generally target the reactive functional groups in cysteine and lysine residues, particularly in the case of larger peptides, and the modification of peptides that do not feature these functionalities is more difficult. Nevertheless, chemists have also been exploring methods that can be applied even to such chemically inert peptides based on recent advances in C–H activation and hydrogen atom transfer (HAT) chemistry. If successful, these strategies would represent a breakthrough in terms of obtaining unusual peptide structures in a time‐ and cost‐effective manner. This review focuses on recent attempts to achieve such ambitious chemical modifications, albeit that these are currently limited to relatively small peptides.

As an alternative to the conventional approach, which combines amino acid monomers in a one‐by‐one fashion to peptide derivatives, the chemical modification of existing peptides has attracted significant attention in recent years. However, such approaches generally target the reactive functional groups in cysteine and lysine residues, particularly in the case of larger peptides, and the modification of peptides that do not feature these functionalities is more difficult. This review focuses on recent attempts to achieve such more ambitious chemical modifications.