UC teams map SARS-CoV-2 RNA–protein sites; blocking them cuts viral replication in cells
Researchers mapped where three viral proteins bind the SARS-CoV-2 RNA genome; blocking these sites in cells reduced replication, an early proof of concept for antiviral targets.
A team from the University of California San Diego School of Medicine and the University of California, Riverside School of Medicine has mapped previously unknown interactions between the SARS-CoV-2 RNA genome and viral proteins, according to today.ucsd.edu. The work, published in Nature Communications, covers three proteins: primase cofactor NSP8, RNA-dependent RNA polymerase NSP12 and nucleocapsid protein N. The authors report that disrupting these interactions significantly reduced viral replication today.ucsd.edu
today.ucsd.edutoday.ucsd.eduOpen source ↗.
The result is described as an early proof of concept for targeting RNA–protein interactions in diseases caused by coronaviruses. It is a laboratory study in cells; no drug was tested.
How the binding sites were mapped
The researchers used enhanced cross-linking and immunoprecipitation (eCLIP). The method surveys the whole genome rather than only regions predicted to be important, so it can reveal unexpected sites today.ucsd.edu
today.ucsd.edutoday.ucsd.eduOpen source ↗. According to the scinexx summary, the mapping was done 6 and 48 hours after infection of African green monkey kidney cells.
One finding concerns the N protein and the 5′ untranslated region at the start of the genome. This region has a complex RNA structure present in many coronaviruses, with functions not fully understood. The interaction with N appears to regulate translation, the process in which RNA is used to make proteins today.ucsd.edu
today.ucsd.edutoday.ucsd.eduOpen source ↗. The team also found a previously unknown interaction between NSP12 and the RNA encoding the viral protein NSP3. The authors suggest that viral RNA may have regulatory roles beyond serving as a template for proteins. How exactly this binding produces its effect has not been fully established.
Blocking the sites in cells
To test the sites, the team used locked nucleic acids (LNAs): short, modified nucleic acid sequences designed to bind specific RNA regions and prevent protein binding. Blocking the interaction sites significantly reduced viral replication in animal cells. Similar results were obtained in human lung cells today.ucsd.edu
today.ucsd.edutoday.ucsd.eduOpen source ↗.
The authors note that some of the proteins and RNA sequences involved are conserved among coronaviruses. Targeting them could therefore depend less on individual viral variants and might work against several coronaviruses. For comparison, the study cites existing antivirals that act on essential viral machinery: remdesivir targets the enzyme that copies the RNA genome, and nirmatrelvir targets proteins that process long viral protein chains.
"The goal is to understand these core interactions so that, eventually, drug developers can develop therapies that specifically target them," said Joy Xiang of UCR School of Medicine. The senior author is Gene Yeo of UC San Diego School of Medicine.
