They say that change takes time. Well, that's not the case for RNA.
The small biological molecule acts like a switchboard operator, capable of changing its shape every few milliseconds so it can manipulate biological functions in the body. It has big jobs to carry out, after all, like copying genetic information into every living cell and activating the immune response.
A new multidisciplinary study from biophysicists and virologists at the UNC School of Medicine challenges this idea of shape-shifting RNA. Helen Lazear, PhD, associate professor of microbiology and immunology, and Qi Zhang, PhD, professor of biochemistry and biophysics, have discovered that a type of RNA in Zika virus, a mosquito-borne virus, can essentially freeze itself in time in an effort to make more copies of itself and further its spread in the body.
Their findings have not only sent ripples through the field of virology, but it has also given researchers new ammo in the fight against RNA viruses. Their study, which was published in Nature Chemical Biology, paves the way for new therapies that can "un-freeze" these RNA structures to combat other mosquito-borne RNA viruses.
"We know that Zika virus and related viruses rely on these very stable RNA structures to replicate," said Lazear. "By adjusting the stability of this RNA in the lab, we showed that we can shorten its lifespan and make it harder for the virus to grow and spread. We're excited to expand on our research to learn more about how these viruses cause human disease and ways to combat them."
A Surprising Discovery
Qi Zhang, PhD, (Left) and Helen Lazear, PhD, standing in front of a nuclear magnetic resonance (NMR) machine.
Researchers in the Qi Zhang's lab made the discovery back in 2017, when they were performing routine imaging experiments using nuclear magnetic resonance (NMR) imaging. The technology, much like an MRI that is used in humans, allows scientists to visualize shapes and motions of biological molecules, such as RNA, DNA, and proteins, in astounding atom-by-atom detail.
However, lab members were quick to realize that the Zika virus RNA was stuck in this configuration for days-approximately one million times longer than other types of RNA.
Further investigation by the Zhang and Lazear labs revealed that this frozen, stable RNA structure plays an important role in viral replication. They found that this particular configuration can effectively put up a "molecular wall" that protects the viral RNA from being degraded by the host cell, altogether enhancing the ability of the virus to make more copies of itself.
Antivirals and Preparing for Emerging Disease
After analyzing the RNA structure and its mechanisms further, researchers have gotten a better understanding of its strength and also its weakness. If researchers can determine how exactly the RNA structure maintains this strong defense, they might be able to develop new therapies that can disrupt that interaction and interfere with further replication of the virus.
Aedes albopictus, one of two mosquito species that carry Zika virus.
Zika virus is just one of many RNA viruses, termed flaviviruses, that are spread by mosquitoes and ticks around the world, including West Nile virus which is found in North Carolina. As a result, researchers are working to develop new and effective vaccines and to learn more about these viruses before they emerge.
"While some flaviviruses are important causes of disease globally, some of these viruses don't currently cause large outbreaks but have the potential to do so in the future," said Lazear.
"It's really important that we learn about these viruses and have the tools to work with them, so that we're ready to respond to future emerging outbreaks."
Revolutionizing How Scientists Understand RNA Molecules
In the field of biochemistry and biophysics, much of their time is spent on analyzing and detailing the shapes of molecular structures. Understanding their shape allows researchers to learn more about their ins-and-outs, such as how they bind to receptors, activate biochemical pathways, or how they function in the body.
Over the last decade, the field has taken a large leap forward with new technologies that can predict molecular structures using AI. However, the latest findings in the Zhang and Lazear labs add a whole new dimension that scientists may need to consider when understanding RNA viruses: time.
"This paper really changed the paradigm of the field," said Zhang, who is also co-director of UNC RNA Discovery Center at the UNC Lineberger Comprehensive Cancer Center. "We need to start appreciating how long these RNA structures live. Perhaps in the future, we could use AI-based technologies that can not only predict space, but also predict lifetime."
Zhang is the leader of a recently launched research initiative, called the RNA-targeted Innovation in Drug Exploration (RIDE), in the UNC Department of Biochemistry and Biophysics and co-director of the RNA Discovery Center. Leveraging their latest knowledge about RNA viruses, Zhang and Lazear will further explore drug targeting in RNA viruses, alongside other experts in microbiology, virology, and biochemistry at UNC-Chapel Hill.
Rhese Thompson, PhD, a recent graduate in the Zhang lab, was lead author on the paper. Other authors include Derek Carbaugh, PhD, and Joshua Nielsen in the Lazear lab, Edgar Faison and Bo Zhao, PhD, in the Zhang lab; Jeffrey Bonin, PhD; Rita Meganck, PhD, in the Marzluff lab; Nathan Nicely, PhD, associate professor of Pharmacology; William Marzluff, Kenan Distinguished Professor of Biochemistry and Biophysics at UNC-Chapel Hill; Aaron Frank, PhD, assistant professor of Chemistry and Biophysics at the University of Michigan, Ann Arbor; Ciara Witt, PhD, in the Frank lab; and Atul Rangadurai, PhD, from Duke University.
Funding for this project came from the Emerging Challenges in Biomedical Research (ECBR) pilot award program from the UNC School of Medicine's Office of Research, the Jefferson-Pilot Award from the UNC School of Medicine, UNC - Chapel Hill, the National Institutes of Health, and the Burroughs-Wellcome Fund.
Researchers would like to acknowledge the Biomolecular NMR Laboratory, which receives funding from the National Cancer Institute of the National Institutes of Health under award number P30CA016086, for spectrometer maintenance and use.
