Hitch chemicals to proteins for a scientific Swiss Army knife

US chemists have developed a powerful method of selectively linking chemicals to proteins, in an advance that could transform the way drugs are developed, proteins are probed and molecules are tracked.

The new technique, called redox activated chemical tagging (ReACT), was developed at the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab). It is believed that it could fundamentally change the process of bioconjugation — the process by which chemicals and tags are attached to biomolecules (particularly proteins).

F Dean Toste, who co-led the study, compared bioconjugation to hitching cargo onto the back of a pickup truck.

“That cargo can be used for many purposes,” he said. “It can deliver drugs to cancerous cells or it can be used as a tracking device to monitor the truck’s movements. We can even modify the truck and change it to an ambulance. This change can be done in a number of ways, like rebuilding a truck or putting on a new hitch.”

Bioconjugation traditionally relies on the amino acid cysteine, often used as an attachment point for tags and chemical groups because it is one of two amino acids that contain sulfur. This provides an anchor for acid-based chemistry and makes it easy to modify. But cysteine is often involved in the actual function of proteins, so ‘hitching cargo’ to it creates instability and disrupts its natural function.

Seeking to circumvent cysteine, scientists have typically turned to methionine — the only other sulfur amino acid available. A key benefit of methionine is that it is a relatively rare amino acid, which allows researchers to selectively target it with fewer side effects and less impact on the biomolecule.

However, methionine has an extra carbon atom attached to its sulfur, which blocks most hitches. The Berkeley researchers developed a new hitch using a process called oxidation-reduction chemistry, which allows cargo to be hitched to the methionine sulfur with this extra carbon still attached.

The team put ReACT to the test by synthesising an antibody-drug conjugate to highlight its applicability to biological therapeutics. They also identified the metabolic enzyme enolase as a potential therapeutic target for cancer, showing that the tool could help home in on new targets for drug discovery. Their results have been published in the journal Science.

“We’ve essentially invented a new type of chemical Swiss army knife for proteins — the first that can be used for the essential and naturally occurring amino acid methionine,” said principal investigator Christopher Chang. “This ReACT method can be incorporated into a variety of different tools depending on what you need it to do. You can mix and match different reagents for a variety of applications.”

ReACT involves the modification of proteins by attaching chemical cargos to the amino acid methionine. It supports a wide variety of fields, spanning fundamental studies of protein function to applications in cancer treatment and drug discovery. Image credit: Shixian Lin/Berkeley Lab.

In the long term, the researchers said, this new bioconjugation tool could be used in:

• nanotechnology, where protein conjugation can help make nanomaterials compatible with air and water, reducing toxicity;
• the creation of artificial enzymes that can be recycled, have better stability and have improved activity and selectivity through chemical protein modification; and
• synthetic biology, where it can be used to selectively make new proteins or augment the function of existing ones.

“This method could also add to the functionality of living organisms by directly modifying natural proteins to improve their stability and activity without making a genetically modified organism that relies on gene editing,” said Chang. “It could have implications for the sustainable production of fuels, food or medicines, as well as in bioremediation.”

Top image courtesy of Andrew Toskin under CC BY 2.0