ISU researcher wins innovation challenge to seek RNA drug targets

Walter Moss and grad student Jake Peterson look at an RNA molecule on a computer screen.

Associate professor of biochemistry, biophysics and molecular biology Walter Moss, left, and graduate student Jake Peterson discuss a computer rendering of an RNA molecule. A research team led by Moss will partner with global drugmaker AstraZeneca to identify segments of RNA structures that could be targets for drug compounds. Photo by Christopher Gannon/Iowa State University. Larger image.

AMES, Iowa — When Walter Moss first began studying RNA structures, it was a somewhat obscure realm of basic science. A handful of RNA-based drug treatments had been approved for specific diseases, but after decades of research, RNA therapeutics continued to have promising potential but limited use.

Then the COVID-19 pandemic happened. Vaccines that harness messenger RNA emerged as an effective protection against the virus, and hundreds of millions of people around the world were immunized with them. That has caused an explosion of interest in RNA, the nucleic acid that puts the genetic code into action and has a wide variety of other functions scientists are still working to grasp, said Moss, an associate professor of biochemistry, biophysics and molecular biology at Iowa State University.

“Finding small bits of RNA sequences that can have medical significance has taken on much bigger importance now,” he said. “It’s gratifying to have that research getting closer to actually helping patients.”

The Moss lab was among nearly 50 RNA research groups to pitch a proposal for the CoSolve innovation challenge, part of AstraZeneca’s Open Innovation program. The Iowa State team’s inventive approach won a 16-month grant to work with AstraZeneca scientists, a project that launches Jan. 12.

The partnership will combine the Moss lab’s expertise in RNA structure, which recently has expanded to three-dimensional modeling, with AstraZeneca’s experience in developing drug compounds and next-generation therapeutics – including cell and RNA therapies. Moss said the hope is that many of the principles of drug design can transfer to RNA, which requires finding “druggable” RNA segments that offer suitable spots for molecules to bind.

“When you get down to the essence of it, an RNA 3D structure is just a shape. It’s got pockets and topography that create places where you should be able to stick therapeutic molecules,” he said.

Finding those molecular landing strips for drug compounds starts by analyzing RNA fragments in the human genome, looking for sequences that are more stable than expected. Such unusual stability suggests evolution has ordered the RNA sequence to fold in a special way, which may have biological importance. These exceptional sequences are then modeled to predict their shapes and tested virtually for their ability to bind drug molecules.

“You find a shape of interest and simulate putting millions of different molecules in these stable spots and wiggling them to see if they’re a good fit,” Moss said.

Moss said he expects his team will learn a lot working with AstraZeneca researchers, especially as his lab extends its RNA structure-finding methods to 3D shapes and molecular interactions.

“I really envision this as a two-way street,” he said.

The project will be the second time Moss has collaborated with a pharmaceutical company, following a two-year partnership with Eli Lilly that began in 2020.

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