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Â鶹ÊÓƵ (SFU) chemistry professor Robert Britton and his team have developed a faster way to build a class of molecules used in many antiviral and cancer treatments. Working with health sciences professor Ralph Pantophlet, they demonstrated the platform’s potential for antiviral drug discovery by screening the resulting compounds against HIV.

Their advance could shorten the process of drug discovery, which matters most when new outbreaks emerge.

The study, , published in Science, focuses on nucleoside analogs (NAs), compounds that closely resemble the building blocks of DNA and RNA. As viruses and cancer cells copy their genetic material to multiply, these molecular look-alikes can disrupt that process. They are already used to treat infections such as HIV and hepatitis.

Making them in the lab, however, creates a major bottleneck. Each new analog typically requires a long and complicated synthesis, which limits how many candidates scientists can create and test.

A team led by Britton, with collaborators at pharmaceutical company Merck, took a different approach. They began with a single, versatile building block that can be produced in large quantities. Then, using a light-driven reaction, they attached a variety of nucleobases to it, much like building multiple variations from a common template. The method can generate libraries of candidate compounds 10 to 100 times larger than before, in weeks rather than months or years.

Using the platform, the team produced more than 70 analogs, most of them new. Pantophlet's lab then screened the compounds against HIV. Three showed activity comparable to approved HIV therapies.

The ability to generate compounds at this speed and scale is critical in antiviral research Compared with painkillers and antibiotics, the world has a relatively limited arsenal of antiviral drugs. Expanding that toolkit is critical for responding to outbreaks such as COVID-19, Ebola and future emerging viruses.

The researchers stress that the three compounds are early laboratory findings. They would need extensive further testing for safety and effectiveness before becoming medicines. The advance lies in accelerating the earliest stage of drug discovery, giving researchers and drug developers a much larger pool of promising compounds to explore.

We spoke to professors Britton and Pantophlet about their research.

How would you explain the light-driven reaction to someone with no chemistry background? Is there an analogy you use with students?

Britton: For molecules to react, they often need to overcome an energy barrier, like pushing a ball over a hill. In this key reaction, light provides the energy needed for the molecules to react together to form a nucleoside analogue.

You have that medicine lacks a good panel of antivirals compared with painkillers and antibiotics. Why has that gap persisted?

Pantophlet: Viruses are particularly difficult to target because they have relatively few components of their own. Instead, they reproduce by entering our cells and using much of the cells’ machinery and raw materials. Researchers must therefore identify the limited number of viral processes that can be disrupted without harming the host cell. Finding compounds that can enter cells, reach the right target and selectively interfere with the virus—while remaining safe for patients—is a substantial challenge. The enormous diversity of viruses adds another difficulty: a drug that works against one virus, or even one viral family, may have little effect on another.

What was the biggest obstacle in making this work, and what was the moment like when you realized it would work?

Britton: The biggest challenge we faced was identifying the versatile building block that would unlock access to a diversity of nucleoside analogues. We spent more than a year making molecules that we thought would provide a foundation for this work, but never did. The ultimate discovery took us all by surprise. We had not thought this molecule would be stable or even something we had the tools to prepare, and it turned out to be easy to prepare and remarkably stable!

If a new viral outbreak happened tomorrow, how would this tool change the way researchers respond?

Pantophlet: Viruses are classified into families whose members share key structural and functional features. As a result, an antiviral developed against a well-studied virus may provide a valuable starting point when a new member of the same family emerges. By studying representative viruses in advance, researchers can establish a foundation of knowledge, drug candidates, and testing methods that can be rapidly mobilized during an outbreak.

Many nucleoside analogues disrupt the enzymes viruses use to replicate their genetic material. The Britton platform enables researchers to generate much larger and more diverse libraries of these compounds in a relatively short time. If a new virus were to emerge, these libraries could be screened rapidly to identify promising candidates. Although rigorous testing would still be required, this approach could substantially accelerate the earliest—and often rate-limiting—stage of antiviral discovery.

What would you like the public to understand about how long drug discovery takes?

Pantophlet: The public often hears about a promising compound when it is first discovered, but that moment marks only the beginning of a long and highly selective process. A candidate must be evaluated for antiviral activity and toxicity, its behavior in the body, its potential for reliable manufacturing, and ultimately, its safety and effectiveness in people. Most compounds do not complete this journey successfully, and the entire process can take many years.

Accelerating drug discovery therefore requires more than rapidly producing new molecules. It also depends on close collaboration between the chemists who create compounds and the scientists who evaluate their antiviral activity, supported by flexible, scalable infrastructure for screening against relevant viruses. This work can shorten the critical early stages of discovery: larger and more diverse compound libraries can be generated and tested sooner, enabling researchers to identify and advance the most promising candidates more efficiently.

For more:

• Robert Britton’s faculty web page and Research Expertise Engine profile.
• Ralph Pantophlet’s faculty web page and  Research Expertise Engine profile.
• Â鶹ÊÓƵchemists​ supercharge antiviral drug discovery.

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