A cell biologist at The Scripps Research Institute (TSRI) has identified the molecular motor that RNA viruses use to copy themselves. The discovery, which also reveals an Achilles' heel of these pathogens, could lead to the development of treatments effective against a wide range of RNA viruses.

The findings are described in the May 10, 2018, issue of the journal _Cell_.

"What's really exciting about this discovery is that it explains why the RNA-dependent RNA polymerase is so inefficient," said TSRI Associate Professor Erica Ollmann Saphire. "Now that we know the molecular basis for this inefficiency, we can envision designing drugs to exploit this weakness and stop RNA virus replication altogether."

RNA viruses, which include influenza viruses, Ebola virus and Zika virus, hijack a cell's molecular machinery to make copies of themselves. As they do, they produce thousands of copies that aren't quite identical.

This imprecision is crucial for the survival of RNA viruses, Saphire said, because it allows them to rapidly evolve. It also prevents people from acquiring lifelong immunity to many of them, such as the flu.

The team made this discovery by using cryo-electron microscopy to capture images of the molecular machinery in action. They saw that the RNA-dependent RNA polymerase motor is prone to stalling.

When the motor stalls, it pauses for a few seconds until another molecule pries it off and allows it to continue moving. This "molecular tug of war" explains the inefficiency of the replication process.

Saphire and her colleagues also discovered that the molecular motor is regulated by two zinc fingers, which are small protein structures that bind to zinc atoms.

"If you genetically mutate either zinc finger, the motor goes into overdrive and the replication process speeds up dramatically," Saphire said. "So the zinc fingers are acting as brakes for replication, which suggests they could be an attractive target for new drugs."

Implications for Drug Design

The researchers believe that drugs to block the zinc finger regulators of RNA viruses could be effective treatments for a wide variety of these pathogens.

"I don't think we could target all RNA viruses with a single drug, but we might be able to target families of viruses with a particular inhibitor," said Saphire. "That would be an important step toward developing broad-spectrum antiviral drugs that could save lives and reduce the threat of pandemics."

In addition to Saphire, authors of the paper, "Cryo-EM Structure of Ebola Virus RNA-Dependent RNA Polymerase," include first author Michael Lo, Jessica Tan, Nicholas P. Anderson and Daniel I. Soukup of TSRI; Erica N. Olson, Robert P. Henderson and Christopher B. Burd of the University of Texas Southwestern Medical Center; Matthew T. Dougherty and David W. Heinz of the University of Pennsylvania; and Karissa A. Johnson and Pei-Yong Shi of the University of Texas Medical Branch.

The research was supported by the National Institutes of Health (grants R01 AI121966, R01 AI120694 and R37 AI106547), the Welch Foundation, the Defense Threat Reduction Agency and the Texas A&M Institute for Pre-Pandemic Preparedness.