Rice University chemists develop cheaper way to synthesize drugs

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

While this phosphate switch is essential for cells, it presents an important issue for drug design. Many drugs, especially those based on biological compounds, have phosphates in their chemical structure. Cells can dephosphorylate these drugs as the body processes them, greatly reducing their effectiveness.”

Hans Renata, Professor of Chemistry, Rice University

The solution to this, though well thought out, 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 Naturethat significantly reduces the cost of adding thiophosphate to chemical structures, opening new avenues for drug design.

“To add thiophosphate to a chemical structure like a drug, you have to use a compound called ATPγS, which is a very expensive molecule,” said Xiangyu Wu, co-first author and 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, however, 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 that with the right enzymes and the right donor molecule, you can definitely 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: Researchers can adapt the process to add thiophosphates to different kinds of chemical structures and in different places.

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

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