Researchers at the University of California, Riverside, and the University of California, San Diego, have identified previously unknown interactions between viral RNA and proteins in SARS-CoV-2, providing potential targets for future antiviral therapies.
Researchers Deploy Enhanced Cross-Linking to Chart Viral RNA Interactions
To examine how viral proteins interact with genetic material, the research team deployed enhanced cross-linking and immunoprecipitation (eCLIP). This method allowed scientists to chart protein-RNA interactions across the entire SARS-CoV-2 genome rather than focusing strictly on pre-selected regions, according to findings published in Nature Communications.
The investigation uncovered two principal molecular relationships. First, researchers spotted an interaction between the nucleocapsid (N) protein and the 5′ untranslated region, a complex RNA structure at the start of the viral genome. This interaction appears to influence translation, the biological process through which viral RNA directs the production of proteins.
Second, the team identified a connection between the RNA-dependent RNA polymerase (RdRp) and the RNA sequence encoding viral protein NSP3. Because RdRp functions as the primary enzyme responsible for copying the viral RNA genome, this link indicates that viral RNA holds regulatory duties beyond acting merely as a template for protein creation.
“Viruses look simpler than humans at first glance, but there’s a lot of underlying complexity to their molecular biology we’re only just beginning to unravel,” said Gene Yeo, a professor of cellular and molecular medicine at UC San Diego. “Our findings suggest that viral RNA may have a more significant role in regulating fundamental cellular processes than we previously understood.”
Targeting Conserved Regions to Prevent Drug Resistance
The rapid evolution of SARS-CoV-2 creates ongoing hurdles for treatments designed to recognize specific, highly mutable viral features such as the spike protein. As mutations accumulate, current therapeutics can lose potency. Conserved regions, by contrast, maintain stability because they perform essential functions the virus cannot discard without losing its ability to survive or replicate.
“SARS-CoV-2 evolves very quickly, so it’s important to understand the really basic and essential machinery of the virus,” said Joy Xiang, an assistant professor of biomedical sciences at UCR’s School of Medicine. “If we target something essential that the virus depends on to function and can’t easily change, the virus is less likely to evolve away from it, which would lead to drug resistance.”
Current antiviral treatments already exploit parts of this essential machinery. Remdesivir interferes with RdRp to block genetic replication, while Paxlovid targets viral proteases. However, the new research aims to disrupt the coordination between viral RNA and proteins directly.
To test if these interaction sites could be blocked therapeutically, researchers used antisense oligonucleotides (ASOs), which are short, modified nucleic acid sequences designed to bind complementary sections of RNA. Experiments demonstrated that applying ASOs to the newly identified sites significantly reduced viral replication in both monkey-derived Vero cells and human lung cells.
Broad-Spectrum Implications for Future Outbreaks
The strategy aligns with wider scientific efforts to prepare for future coronavirus outbreaks by targeting stable viral components rather than shifting variants. A 2024 review published in Nature Reviews Microbiology emphasized broad-spectrum antivirals against conserved components as a core pillar of outbreak preparedness.
Because several proteins and RNA sequences identified in the study remain conserved across multiple coronavirus species, investigators suggest the approach could yield treatments effective against various strains or even other animal viruses capable of spilling over into humans.
However, the work remains in an early preclinical phase. Because experiments have so far been limited to cell cultures, subsequent animal studies are required to determine whether disrupting these specific RNA-protein interactions is safe and effective in living organisms.
Xiang is currently analyzing comparable RNA-protein interactions in other viral pathogens, while Yeo’s laboratory continues refining technologies to map these molecular relationships across different families of viruses.
“The goal is to understand these core interactions so that, eventually, drug developers can develop therapies that specifically target them,” Xiang said. “We need to understand the fundamental biology of these viruses instead of just being reactive to outbreaks.”
Frequently Asked Questions About Conserved Viral Targets
What makes conserved regions different from other parts of the SARS-CoV-2 genome?
Conserved regions maintain stability because they execute essential survival and replication functions that the virus cannot alter without damaging its own viability. Highly mutable sections, such as the spike protein, change frequently as the virus evolves.
How do antisense oligonucleotides interfere with viral replication?
Antisense oligonucleotides are short, modified nucleic acid sequences built to bind complementary sections of viral RNA. By attaching to these specific sites, they block interactions with other molecules and disrupt the viral life cycle.
Have these targeted treatments been tested in humans?
No. The current research functions as an early proof of concept conducted exclusively in cell cultures using Vero cells and human lung cells. Animal testing remains a necessary next step before human clinical trials can begin.
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