May 13, 2021 ~ ETH Zurich ~ Dominik Theler

The Achilles heel of the Coronavirus

SARS-​CoV-2 is critically dependent on a special mechanism for the production of its proteins. A collaborative team led by a research group at ETH Zurich obtained molecular insights into this process and demonstrated that it can be inhibited by chemical compounds, thereby significantly reducing viral replication in infected cells.

Viruses require the resources of an infected cell to replicate and then infect further cells, and transfer to other individuals. One essential step in the viral life cycle is production of new viral proteins based on the instructions in the viral RNA genome. Based on these construction plans, the cell’s own protein synthesis machine, called the ribosome, produces the viral proteins.

In the absence of viral infection, the ribosome moves along the RNA in strictly defined steps, reading three letters of RNA at a time. This three-​letter code defines the corresponding amino acid that is being attached to the growing protein. It almost never happens that the ribosome slips one or two RNA letters forward or backward instead of following the regular three-​letter steps. When such a slip of the ribosome occurs, it is called “a frameshift,” and it leads to incorrect reading of the genetic code.

Frameshifting almost never happens in our cells. It would lead to dysfunctional cellular proteins; however, certain viruses, such as coronaviruses and HIV, depend on a frameshifting event to regulate levels of viral proteins. For example, SARS-​CoV-2 – the virus that causes COVID-​19 – is critically dependent on frameshifting promoted by an unusual and intricate fold in the viral RNA.

Therefore, since frameshifting is essential for the virus but it almost never happens in our organism, any compound that inhibits frameshifting by targeting this RNA fold could potentially be useful as a drug to combat infection. However, so far, there is no information on how the viral RNA interacts with the ribosome to promote frameshifting, which would be important for drug development.

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