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

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.