New chemical reaction enables precise functionalization of peptides and proteins

Pharmaceutical scientists at the National University of Singapore (NUS) have developed a novel chemical reaction that enables the precise functionalization of peptides and proteins. This approach could provide a useful tool for bioconjugation and drug discovery.

Chemical modification of biomolecules is a powerful strategy for augmenting their functions. For example, antibody-drug conjugates use targeted antibodies to deliver highly cytotoxic drugs directly to tumour sites, while receptor ligand peptides armed with MRI agents improve medical imaging. However, selectively modifying proteins remains a significant challenge. Proteins are large molecules with many functional groups of similar reactivity, making it difficult to achieve precise modifications. Often, these reactions lead to complex mixtures that are difficult to control, poorly reproducible, and may include components with unintended effects.

The team led by Assistant Professor Alexander VINOGRADOV from the NUS Department of Pharmacy and Pharmaceutical Sciences and Professor Hiroaki SUGA from the University of Tokyo, Japan have developed a palladium-mediated reaction that overcomes some of these challenges. Their method works under ambient conditions in water and relies on affordable reagents to achieve efficient and selective bioconjugation using widely available boronic acid derivatives. The conjugation chemistry specifically targets peptides and proteins containing dehydroalanine, a non-canonical but common amino acid found in many proteins and peptidic secondary metabolites.

Beyond enabling precise protein modification, the reaction also facilitates the synthesis of peptides containing dehydrophenylalanine-an unusual amino acid that helps peptides fold into stable, structurally unique shapes. This could be valuable in peptide drug discovery, where researchers seek peptides with rigid secondary structures that improve metabolic stability and bioavailability.

The study, published in the Journal of the American Chemical Society on 21 February 2025, demonstrates the simplicity and robustness of this new coupling method. The researchers successfully applied it to peptides produced using cell-free translation systems, providing a fast and efficient route to dehydrophenylalanine-containing structures-compounds that, until now, had lacked a straightforward method for synthesis.

mRNA display has been a tremendously powerful tool for identifying bioactive peptides. We are hoping our chemistry will help us discover compounds with high drug-likeness, taking the technique to the next level."

Asst Prof Alexander Vinogradov, NUS Department of Pharmacy and Pharmaceutical Sciences

Looking ahead, the team aims to integrate their chemistry with mRNA display, a widely used drug discovery technique for identifying peptide inhibitors of therapeutically relevant proteins. By incorporating structurally privileged peptides into the process, they hope to accelerate the discovery of drug-like compounds.