Biospecific Chemistry for Covalent Linking of Biomacromolecules

Interactions among biomacromolecules, predominantly noncovalent, underpin biological processes. However, recent advancements in biospecific chemistry have enabled the creation of specific covalent bonds between biomolecules, both in vitro and in vivo. This Review traces the evolution of biospecific chemistry in proteins, emphasizing the role of genetically encoded latent bioreactive amino acids. These amino acids react selectively with adjacent natural groups through proximity-enabled bioreactivity, enabling targeted covalent linkages. We explore various latent bioreactive amino acids designed to target different protein residues, ribonucleic acids, and carbohydrates. We then discuss how these novel covalent linkages can drive challenging protein properties and capture transient protein–protein and protein–RNA interactions in vivo. Additionally, we examine the application of covalent peptides as potential therapeutic agents and site-specific conjugates for native antibodies, highlighting their capacity to form stable linkages with target molecules. A significant focus is placed on proximity-enabled reactive therapeutics (PERx), a pioneering technology in covalent protein therapeutics. We detail its wide-ranging applications in immunotherapy, viral neutralization, and targeted radionuclide therapy. Finally, we present a perspective on the existing challenges within biospecific chemistry and discuss the potential avenues for future exploration and advancement in this rapidly evolving field.