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NSP1 suppresses protein production in the cell

Researchers have had a viral protein known as NSP1 in their sights for a long time. This is the first viral protein to be produced following infection of the host cell. “NSP1 suppresses protein production in the cell without impairing the synthesis of viral proteins,” says Marina Chekulaeva. “Until now, there had been very contradictory hypotheses about how this worked. We decided to explore this mechanism with Lucija Bujanic, the first author of the manuscript who joined the lab during the lockdown to do her Master thesis.”

Marina Chekulaeva and her team have now successfully unravelled this process. Scientists already knew that the NSP1 protein binds to the ribosomes which serve as the cell’s protein factories. To be more precise, it anchors itself in the tunnel through which the messenger RNA (mRNA) enters the ribosome to allow the protein-making instructions to be read and then translated into proteins. This has the effect of blocking the ribosome to an extent that cellular mRNAs can no longer enter the protein factory and the cell cannot synthesize important cellular protein molecules. This in turn suppresses the immune response.

Stem loop serves as entry ticket

However, viral mRNAs also need access to the protein factories so that new viral particles can be produced. So how do they get around the blockade the virus has created? Marina Chekulaeva and her team have discovered that particular nucleotides in a special structure in viral mRNA, known as a hairpin or stem loop, are involved. This hairpin seems to function as a kind of entry ticket: it interacts with NSP1, which permits access into the ribosome, allowing the viral protein to be synthesized.

“This means that we've discovered three possible approaches to antiviral treatments,” says Chekulaeva. One possibility would be to target the NSP1 protein itself to prevent it from interacting with the ribosome. Alternatively, the interaction between the NSP1 protein and the viral mRNA could be suppressed. For example, the point at which NSP1 interacts with the stem loop could be blocked.

Another conceivable approach would be to specifically eliminate the viral mRNA. With this in mind, Chekulaeva and her team have produced oligonucleotides that have been chemically modified to stabilise them. These bind to the stem loop, creating an RNA-DNA hybrid that is eliminated by the cell. Since this stem loop is specific for viral mRNA, this intervention is very specific – it does not affect the cellular mRNA, and therefore does not impair protein synthesis in the infected cell. “It’s also a very important structure, which we can assume with a fair degree of confidence undergoes very little mutation,” says Chekulaeva. “So it's unlikely that any resistance would develop.”

All three possibilities are potentially promising – at least in experiments in the petri dish. More research is needed to establish which of them offers the greatest potential for effective treatments.