A new chemical reaction to perfect protein engineering
Scientists have developed a palladium-mediated reaction for precise protein modification, overcoming key challenges in bioconjugation and accelerating the drug discovery pathway.
Scientists at the National University of Singapore (NUS; Queenstown, Singapore) have developed a new chemical reaction that allows precise protein and peptide modification. Using palladium-mediation, their method overcomes current challenges in achieving precise protein modifications, with the potential to accelerate drug discovery and the development of next-generation therapeutics.
The ability to chemically modify biomolecules is fundamental to advancing modern medicine, enabling the development of targeted therapies and improved diagnostic tools. From antibody-drug conjugates that precisely deliver chemotherapy to cancer cells, to specialized peptides that enhance imaging techniques for better disease detection—the importance of chemical modifications for therapeutic applications reaches far and wide. Alas, modifying proteins with precision remains a significant challenge due to their intricate structures and the presence of numerous functional groups with similar reactivity. Conventional methods often result in complex mixtures that are hard to control, leading to inconsistent outcomes.
Addressing this longstanding challenge, a research team led by Alexander Vinogradov (an Assistant Professor in the Department of Pharmacy and Pharmaceutical Sciences at NUS) and Hiroaki Suga (a Professor in the Department of Chemistry at the University of Tokyo; Japan) developed a palladium-mediated reaction that enables highly selective and efficient protein modification.
You may also be interested in:
- Streamlining the creation of oligonucleotide conjugates
- Technology Digest: the trials and triumphs in oligonucleotide bioanalysis
- The need for HRMS for quantitation of ADCs vs. QqQ: an interview with Megan Cooley
The new technique employs palladium catalysis and affordable boronic acid derivatives to selectively modify peptides and proteins containing dehydroalanine—a common and biologically relevant amino acid that is often overlooked. This approach not only streamlines bioconjugation but also enables the synthesis of structurally rigid peptides, which are highly sought after in drug development due to their improved stability and bioavailability.
“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,” stated Vinogradov.
Highlighting the method’s reliability in modifying peptides from cell-free translation systems, the study exemplifies a fast an efficient approach to synthesizing bioactive molecules that were previously challenging to produce. This breakthrough marks a major step forward in precision protein engineering, offering an exciting new tool for researchers in biomedicine and pharmaceutical sciences.
The team now aim to combine their new reaction with mRNA display technology, a popular approach for identifying peptide-based inhibitors of therapeutically relevant proteins. By integrating uniquely structured peptides into their approach, they aim to advance drug discovery, with the potential to develop novel therapies for a range of diseases.
