Scientists at ETH Zurich have developed a new chemical technique that could make it far easier to build complex proteins used in modern medicines, including next-generation cancer therapies.
The research, published in the journal Science, introduces a protein-assembly method that works at concentrations thousands of times lower than those required in conventional protein synthesis. The advance could help scientists produce proteins that are normally difficult to manufacture because they clump together or dissolve poorly in water.
Chemical synthesis of proteins typically involves stitching together smaller fragments of peptides created through solid-phase synthesis. But the process often runs into trouble when the fragments are large or highly hydrophobic, say experts. Such pieces tend to aggregate, making them difficult to join into complete proteins.
The ETH Zurich team, led by organic chemist Jeffrey W. Bode, has now developed a new peptide ligation strategy based on the unique chemical properties of boron-containing molecules. Their approach enables protein fragments to link together efficiently in water even at extremely low concentrations.
For your daily dose of medical news and updates, visit: HEALTH
At the heart of the method are two specially designed chemical groups attached to peptide fragments: a potassium acyltrifluoroborate (KAT) group on the carboxyl end of one fragment and a hydroxylamine group on the amino end of another.
When these two fragments meet, they react rapidly and selectively to form an amide bond, the fundamental chemical link that holds proteins together.
Traditional peptide-coupling reactions typically require relatively high concentrations of reactants to proceed efficiently. By contrast, the KAT-based reaction works at micromolar concentrations, making it possible to assemble proteins even when the fragments are prone to aggregation, as per the research paper.
To make the strategy compatible with existing laboratory techniques, the researchers also designed a protecting-group system that allows KAT-modified amino acids to be incorporated during standard solid-phase peptide synthesis.
This means the new chemistry can be integrated into conventional protein-synthesis workflows.
One of the biggest obstacles in chemical protein synthesis is handling fragments that are poorly soluble or highly hydrophobic. Such fragments often clump together before they can be joined, preventing the construction of full-length proteins.
The ETH Zurich team addressed this by designing chiral zwitterionic organoboron complexes that temporarily mask KAT groups during synthesis. These complexes exhibit an unusual nitrogen–carbon–boron connectivity but remain stable throughout peptide synthesis and can later be unmasked without altering the protein’s structure.
Using this approach, the researchers successfully assembled difficult proteins that are known to aggregate. Among them was the immunoglobulin V domain of programmed death ligand-2 (PD-L2), a protein involved in immune signalling.
PD-L2 is part of the PD-1 immune checkpoint pathway, which plays a crucial role in how cancer cells evade the immune system. Proteins from this pathway are major targets in modern immunotherapies.
By enabling the synthesis of aggregation-prone proteins such as PD-L2, the new method could help scientists study immune checkpoint mechanisms in greater detail and design improved therapeutic molecules.
The technique may also benefit the development of antibody–drug conjugates (ADCs), targeted cancer drugs that deliver toxic payloads directly to tumour cells while minimising damage to healthy tissue.
Chemical protein synthesis allows scientists to design proteins with highly precise structures, including modifications that are difficult to achieve using biological systems.
By enabling protein assembly at much lower concentrations, the boron-based chemistry could significantly expand the range of proteins that can be built in the laboratory.
Researchers say the approach establishes organoboron chemistry as a powerful tool for protein synthesis, particularly for large or aggregation-prone biomolecules that have previously been difficult to produce.
As peptide and protein therapeutics continue to grow as a major category of modern medicines, advances like this could accelerate the development of new drugs across fields ranging from oncology to immunology.
