Study identifies new targets for antiviral drugs against coronaviruses

A study led by researchers at the University of California San Diego School of Medicine and University of California, Riverside (UCR) School of Medicine has identified new targets for antiviral drugs against coronaviruses, including SARS-CoV-2, the virus that causes COVID-19. These new targets could help scientists discover treatments that are less vulnerable to the rapid evolution of these viruses.

"There's so much we don't know about coronaviruses at a fundamental biological level, and everything we learn gives us more options when developing treatments," said senior study author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine, director of the Center for RNA Technologies and Therapeutics and director of the Sanford Stem Cell Innovation Center. "If we want to stay ahead of these viruses, we have to understand them from the inside out."

The research, published in Nature Communications, mapped previously unknown interactions between the RNA that makes up the SARS-CoV-2 genome and proteins involved in the virus's replication and regulation. The team identified specific RNA binding sites for three proteins – primase cofactor (NSP8), RNA-dependent RNA polymerase (NSP12) and nucleocapsid (N) - and found that disrupting these interactions significantly reduced viral replication.

The results offer an early proof of concept for targeting RNA-protein interactions as a treatment strategy for diseases caused by coronaviruses, including COVID-19.

Joy Xiang, PhD, assistant professor of biomedical sciences, UCR School of MedicineSARS-CoV-2 evolves very quickly, so it's important to understand the really basic and essential machinery of the virus. 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 drugs already illustrate the value of targeting essential viral machinery. Remdesivir targets the enzyme that copies the virus's RNA genome, while nirmatrelvir targets viral proteins involved in processing the long protein chains produced during infection.

The researchers used a technique known as enhanced cross-linking and immunoprecipitation, or eCLIP, to survey the viral genome and determine where viral proteins interact with RNA. Rather than examining only regions previously predicted to be important, this approach allowed the researchers to map interactions across the whole genome and identify unexpected sites.

One finding involved the N protein and a region at the beginning of the viral genome known as the 5′ untranslated region. This region contains a complex RNA structure that is present in many coronaviruses, but whose precise functions are not fully understood. The researchers found that its interaction with the N protein appears to regulate translation, an essential process in which RNA is used to make proteins.

The researchers also identified a previously unknown interaction involving NSP12 and the RNA encoding viral protein NSP3. This finding suggests that viral RNA may play regulatory roles beyond simply serving as a template for producing proteins.

"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 Yeo. "Our findings suggest that viral RNA may have a more significant role in regulating fundamental cellular processes than we previously understood."

The researchers next tested whether the newly identified regions could be disrupted using locked nucleic acids (LNAs) - short, modified nucleic acid sequences designed to bind specific regions of RNA, blocking these regions from interacting with proteins. Blocking the interaction sites significantly reduced viral replication in animal cells.

The team found similar results in human lung cells, providing additional evidence that the interactions could be relevant to human infection. Their findings suggest that targeting conserved viral processes can work across diverse cells, organs, and host organisms, which is a crucial factor in preparing for future viral pandemics, which often begin when a virus jumps from animals to humans.

The research also points toward the possibility of developing treatments that could work against multiple coronaviruses. Because some of the proteins and RNA sequences involved in these viral life cycle processes are conserved among coronaviruses, targeting them could be less dependent on the emergence of individual viral variants.

"The goal is to understand these core interactions so that, eventually, drug developers can develop therapies that specifically target them," Xiang said.

According to the researchers, the broader significance of the research also extends beyond COVID-19 and the development of a single drug.

"We need to understand the fundamental biology of these viruses instead of just being reactive to outbreaks," Xiang said. "There's value in studying these biological differences, because that understanding can give us new opportunities to develop better treatments."

Source:

University of California San Diego

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