Palladium-mediated reactions enable precise engineering of peptides and proteins

Pharmaceutical scientists at the National University of Singapore (NUS) have developed a new chemical reaction that allows for accurate functionalization of peptides and proteins. This approach may provide useful tools for bioformulation and drug discovery.

Chemical modification of biomolecules is a powerful strategy to enhance their function. For example, antibody drug conjugates use target antibodies to deliver highly cytotoxic drugs directly to the tumor site, whereas receptor ligand peptides equipped with MRI agents improve medical imaging.

However, selective protein modifications remain an important issue. Proteins are large molecules with many similarly reactive functional groups, making accurate modifications difficult to achieve. In many cases, these reactions lead to complex mixtures that are difficult to control, less reproducible, and can contain components with unintended effects.

A team led by Assistant Professor Alexander Vinogradov of the Ministry of NUS Pharmacy and Pharmaceutical Sciences and Professor Hyroaki Suga of the University of Tokyo developed a palladium-mediated response to overcome some of these challenges.

Their methods work under ambient conditions in water and rely on affordable reagents to achieve efficient and selective biocooperative joints using widely available boronic acid derivatives. Conjugation chemistry specifically targets peptides and proteins containing dehydroalanine, a non-standard and common amino acid found in many proteins and peptidine secondary metabolites.

In addition to allowing accurate protein modification, the reaction promotes the synthesis of peptides containing dehydrophenylalanine. This is an unusual amino acid that helps the peptide fold into a stable, structurally unique shape. This may be valuable in peptide discovery where researchers seek peptides with rigid secondary structures that improve metabolism stability and bioavailability.

This study, published in the Journal of the American Chemical Society on February 21, 2025, demonstrates the simplicity and robustness of this new coupling method. The researchers successfully apply it to peptides generated using cell-free translation systems, providing a rapid and efficient route to dehydrophenylalanine-containing structures.

ASST. Professor Vinogradov said, “mRNA display has been a very powerful tool for identifying biologically active peptides. We hope that our chemistry will discover highly drug compounds and take our techniques to the next level.”

The team aims to integrate chemistry with mRNA display, a widely used drug discovery technology to identify peptide inhibitors of therapeutically relevant proteins. By incorporating structurally privileged peptides into the process, they want to accelerate the discovery of drug-like compounds.