Researchers at the University of California, Riverside, and the University of California, San Diego, have mapped previously unknown interactions between SARS-CoV-2 RNA and proteins involved in viral replication and regulation. The findings could help guide the development of antiviral treatments aimed at parts of the virus that are less likely to change rapidly.
The study, published in Nature Communications, focused on interactions involving the RNA-dependent RNA polymerase, or RdRp, and the nucleocapsid, or N, protein. These proteins are essential to the virus’s life cycle. Experiments showed that disrupting specific interaction sites significantly reduced viral replication.
The researchers used enhanced cross-linking and immunoprecipitation, known as eCLIP, to examine interactions across the viral genome. Unlike approaches that focus only on regions predicted in advance to be important, this method allowed the team to identify previously unrecognized sites.
One interaction involved the N protein and the 5′ untranslated region at the beginning of the viral genome. This region contains a conserved RNA structure found among coronaviruses, and the study indicates that its interaction with N may influence translation, the process through which viral RNA directs the production of proteins.
The team also identified an interaction between RdRp and RNA encoding the viral protein NSP3. According to the researchers, this result suggests that viral RNA may have regulatory functions beyond acting as a template for protein production.
To test whether the sites could be targeted, the researchers used antisense oligonucleotides, which are short modified nucleic acid sequences designed to bind specific RNA regions. Blocking the identified interactions reduced viral replication in Vero cells, derived from African green monkey cells, and produced similar results in human lung cells.
The findings support the idea of targeting conserved elements of the viral life cycle instead of rapidly changing features such as the spike protein. Existing antiviral drugs illustrate this strategy: remdesivir targets RdRp, while Paxlovid targets viral proteins involved in processing long protein chains produced during infection.
The researchers emphasized that the work remains an early proof of concept. The experiments were conducted in cell cultures, and animal studies will be needed to determine whether the approach could lead to a treatment.
Because some of the RNA sequences and proteins involved are conserved among coronaviruses, the researchers said the strategy could eventually support therapies active against multiple coronaviruses rather than individual variants. Joy Xiang, an assistant professor of biomedical sciences at UCR, is continuing to study similar RNA–protein interactions in other viruses, while Gene Yeo’s group at UC San Diego is developing related technologies.
Sources: Phys.org.