Scientists streamline creation of nucleoside analogs, a group of life-saving molecules

A team of researchers has found a quicker and more efficient way to create nucleoside analogs, a type of small molecule that can be used in treatments for everything from cancer to viral diseases.

“Nucleoside analogs are among the most important molecules to the advancement of modern medicine,” says Michael Meanwell, assistant professor in the Department of Chemistry and corresponding author of a paper published in Nature Communications describing the new process.

“They’re used as antivirals, as cancer therapeutics, in gene therapy. The first two drugs brought to market for treating COVID-19 were both nucleoside analogs.”

Meanwell and his team focused their approach on C4ʹ-modified nucleoside analogs, a particular subclass of these molecules. A few antiviral drugs within this subclass are already in clinical trials, highlighting their potential. But the issue is that “these types of nucleosides have been notoriously hard to make,” Meanwell explains.

“Part of it has to do with the chemistry used to make them—it’s mostly based on chemistry from 50, 60 years ago, and the advancements in modern organic chemistry have not yet been fully translated to this field of research.”

Until now, the most common ways to make these modified nucleoside analogs required a process taking anywhere from nine to 16 steps. The new approach requires just five steps.

Additionally, existing methods were all non-modular, meaning that making different analogs required designing entirely different routes. It would take a month or more to create just one molecular compound in this way. The new process is modular, so multiple analogs can be made at the same time—an advantage for researchers experimenting with different potential therapeutics.

“By streamlining the process, the barrier now is so much lower to doing drug discovery especially for academic labs working in this area,” says Meanwell. “You can make all the different analogs you want, the chemistry is so much easier, and it reduces the amount of time needed.”

“The breadth of molecules we can make with this one process is truly unprecedented,” he adds.

Nucleosides are fundamental building blocks of DNA, and nucleoside analogs are simply modifications of those structures, explains Meanwell. “They inhibit the same processes associated with cell growth and cell replication that cancer cells and viral diseases take advantage of—by inhibiting them, you can treat those diseases.”

Over the past few decades, nucleoside analogs have been used in treatments for AIDS, Ebola, respiratory syncytial virus (RSV), hepatitis, and many more diseases and infections. A more efficient and effective way to manufacture these powerhouse molecules could pave the way for countless new therapeutics for a vast range of health conditions.

“It sounds like hyperbole, but they can treat such a broad range of diseases,” says Meanwell. “They really stretch across so many different areas of health.”

“C4ʹ-modified nucleoside analogs are so important medicinally because of the wide range of disease pathologies they can intercept,” says lead author Thirupathi Nuligonda. “Now, we have a modular approach to synthesize this important class of nucleoside.”