Pharmaceutical drugs often rely on chemical compounds found in the body. Take phosphate, a common compound cells use as a chemical switch. In a process called phosphorylation, cells can add a phosphate to a molecule and turn its function on. When the function is no longer needed, cells can remove the phosphate through dephosphorylation, turning the molecule back off. 

“While this phosphate switch is necessary for cells, it presents a significant issue for drug design,” said Hans Renata, a professor of chemistry at Rice University. “Many drugs, especially ones that are based on biological compounds, have phosphate in their chemical structures. Cells can dephosphorylate those drugs as the body processes them, significantly reducing their efficacy.” 

The solution to this, though well-studied, is prohibitively expensive: thiophosphate, a phosphate analog that acts similarly to phosphate but is much more difficult to remove. Renata’s team recently developed a method, published in Nature, that significantly reduces the cost of adding thiophosphate to chemical structures, opening up new pathways for drug design. 

“To add thiophosphate to a chemical structure like a drug, you need to use a compound called ATPγS, which is a very expensive molecule,” said Xiangyu Wu, co-first author and a postdoctoral fellow in the Renata lab. “Every time we wanted to add a thiophosphate, we had to use a new ATPγS, and each ATPγS was extremely expensive — too expensive to use in anything but the smallest amounts.” 

ATPγS is an analog of ATP, a molecule that adds phosphates to chemical structures. Unlike ATPγS, though, researchers have developed methods to recycle ATP, greatly reducing the cost of each phosphorylation. With this approach, instead of requiring one molecule for each phosphorylation event, each ATP molecule can be used over and over again.  

“Since ATP and ATPγS are so similar, we decided to see if we could adapt the ATP recycling process for ATPγS,” said Yu Fu, a graduate student in the Renata lab and co-first author. “It turns out with the right enzymes and the right sacrificial donor molecule, you absolutely can recycle ATPγS.” 

Their recycling process requires only a small amount of ATPγS to add thiophosphates to a large number of chemical compounds, greatly reducing the cost of each reaction. And it’s flexible: The researchers can adjust the process to add thiophosphates to different kinds of chemical structures and at different spots. 

“We were able to use this process to cheaply add thiophosphates to several different classes of drugs, from small molecules to macromolecules,” Renata said. “We have exciting preliminary results that suggest making a class of drugs called antisense oligonucleotides, which rely heavily on phosphates. Our recycling method could lead to a more efficient and economical way to prepare these drugs, which are often used to treat genetic diseases.”

This work was funded by the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable research grant, Welch Foundation (C2159), and the Cancer Prevention and Research Institute of Texas (RR220087).

Journal

Nature

DOI

10.1038/s41586-026-10895-9