New method for selective protein modification in living systems could advance cancer research

A research team has developed an innovative technique that enables precise modification of specific proteins within complex biological environments. The work was led by Professor Seung Soo Oh and Dr. Hyesung Jo from the Department of Materials Science and Engineering at POSTECH (Pohang University of Science and Technology), and is featured in the Journal of the American Chemical Society.

Proteins are essential components of our bodies and play crucial roles in disease diagnosis and treatment research. Bio-conjugation techniques utilizing proteins, such as attaching fluorescent markers to identify cancer cells, are actively advancing disease diagnosis and drug development research.

However, existing methods have significant limitations—they often apply only to a narrow range of proteins, require genetic modifications, or risk damaging protein function due to nonspecific modifications. Most challenging of all has been the selective modification of specific proteins in live biological systems.

To address these challenges, the research team discovered a novel approach. They developed a technique that combines deoxyoxanosine (dOxa) with aptamers, nucleic acid-based molecular recognition agents, enabling precise modification of desired sites on specific proteins.

Using this method, the team successfully attached dOxa to just one of 45 possible reactive sites on a target protein. The dOxa compound proved approximately one million times more stable than conventional biomodification reagents (NHS ester), remaining stable for over a month at room temperature and achieving nearly 100% conjugation efficiency within four hours in biological environments.

Notably, the researchers succeeded in bio-orthogonal labeling of two key cancer biomarker proteins—PTK7 and nucleolin—in living cells. This achievement allowed them to observe protein movements in real-time and elucidate the role of these marker protein receptors in cancer cell growth processes. This marks the first successful modification of specific native proteins in biological environments without compromising their functionality.

This technology is expected to have applications beyond cancer diagnosis and treatment. It could pave the way for next-generation antibody-drug conjugates (ADCs) targeting specific cancer cells, bioimaging technologies that clearly distinguish cancerous tissues, and personalized precision treatments that maximize therapeutic effects by regulating specific proteins. Additionally, by precisely modifying specific protein sites to regulate enzyme function, it could make significant contributions to drug development and biological function research.

Professor Oh highlighted the broad impact of this technology, stating, “This technology will be widely utilized in fields such as protein-based therapeutics, bioimaging, and targeted drug delivery.”

Dr. Jo, the first author, added, “We’ve presented an approach that can precisely modify specific proteins as desired. Moving forward, we plan to explore applications in monitoring the unknown mechanisms of living cells and ADC development.”