Viruses must hijack their hosts’ cellular machinery to make more viruses, so preventing this hijacking could lead to a host of new treatments for viral diseases. However, much is unknown about how the viruses actually accomplish their takeover. Scientific understanding is especially murky for RNA viruses, which use RNA as their genetic material, rather than DNA like animals. These viruses’ RNA serves as their genome and also codes directly for viral proteins.

With support from an NSF CAREER Award, Deepak Koirala, assistant professor of chemistry and biochemistry, has been working on figuring out how enteroviruses, a large group of RNA viruses, replicate their RNA genomes. Enteroviruses include viruses that cause polio, the common cold, and many more diseases that affect humans and other animals. Now Koirala has received a five-year, $1.8 million grant from the National Institutes of Health to solve another part of this puzzle: How do these viruses commandeer proteins in the host cell to produce viral proteins? The cell must build these viral proteins before the virus can replicate.

A new biological mechanism?

When a cell makes its own proteins, the cellular mRNA, a type of RNA that carries the instructions for building proteins, interacts with the protein-building machinery via a special structure at one end called a “cap,” Koirala explains. Enteroviral mRNAs lack this cap—and yet they are still perfectly capable of forcing the cell to do their bidding. Koirala is trying to figure out how.

Koirala has been studying unique structures at the ends of viral RNAs for their role in replication, but they may be doing double duty by initiating protein production as well, he believes. Koirala and his team, which includes undergraduate and graduate students, will use a technique called X-ray crystallography to deduce the precise molecular makeup of these special RNA structures.

At the same time, they will run experiments to learn how the structures interact with the cellular machinery. These two lines of investigation complement one another. “If we have the structure, that would allow us to pinpoint the critical nucleotide or amino acid that is important for the interaction,” Koirala says. “And then we can mutate that one, to see how that changes the interaction.”

By using a range of techniques, the team seeks to determine what the structures look like and how they work in the cell. “It could be a new biological mechanism we’ve never seen before,” Koirala says.

The team already has some early data supporting their goals, Koirala says. A related publication is under review at a top-tier academic journal. Several lab members are authors on the paper—including three undergraduates. “We are really excited about that,” Koirala says.

One drug, many targets

The project is likely to end up supporting other researchers, as well.  In the course of the team’s work, “We are developing tools that facilitate our understanding of these RNA structures,” Koirala says. “The tools we develop may be useful not only for the particular system we are working on, but they could be useful in general for many other RNA structures in other fields of research.”

In addition, RNA structures found in one species of enterovirus are very similar to those found in other enteroviruses that cause different diseases—even some that infect very different kinds of organisms, Koirala discovered. That opens the door to developing antiviral treatments that are able to target many different viruses. 

With the RNA structures in hand, the next step might be to use artificial intelligence to screen for other molecules that bind to the structures, preventing the viruses from taking over the cell and causing illness. Scientists could then take steps to develop new drugs using these molecules. 

“Once we understand the structure, and we have a better understanding of the mechanism, we can better design drugs,” Koirala says. “But right now we are at the fundamental level of how these things even work.”

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