According to a new paper published online in the journal Science 13, a team of researchers from the Technical University of Zurich, the University of Bern, the University of Lausanne and the University of Cork in Ireland have identified the “Achilles heel” of coronaviruses, including the new coronavirus (CCA virus). For the first time, the research has successfully revealed the interaction between the viral genome and the ribosome during the “code shifting” process, and found that the virus has “fine control” over the ribosome “code shifting” process, which is expected to This is expected to facilitate the development of drugs that inhibit viral replication by interfering with the “code-shifting” process.
Viruses need to infect cells in order to replicate themselves, and then infect other cells to further infect other individuals. An important step in the life cycle of a virus is to use the cell’s own ribosomes to synthesize the proteins it needs. According to this “plan,” the ribosomes synthesize new viral proteins according to instructions in the viral RNA genome.
In a healthy, uninfected cell, the ribosome moves “step by step” along the RNA, reading three RNA letters at a time. This three-letter code defines the corresponding amino acids that are attached to the growing protein. Sometimes, the ribosome does not follow the regular step of reading three letters, but misses one or two RNA letters. This misalignment of the ribosome is called “code shifting,” which causes the ribosome to read the genetic code incorrectly.
In healthy cells, “code shifting” can lead to dysfunctional cellular proteins. However, some viruses, such as coronaviruses and HIV, rely on “code shifting” to regulate the levels of viral proteins. For example, neo-coronaviruses rely heavily on their RNA folding-induced “shifts” for protein synthesis.
Therefore, because “code shifting” is essential for viruses, any compound that inhibits “code shifting” by targeting RNA folding could potentially serve as a therapeutic agent for infections. However, there is no information to date on how viral RNA interacts with ribosomes to facilitate “code shifting.
Through complex biochemical experiments, the researchers managed to capture ribosomes at the “code-shifting” site of the neo-coronavirus RNA genome. Then, cryo-electron microscopy revealed that the viral RNA forms a pseudoknot structure that rests at the entrance of the ribosomal mRNA channel, creating tension in the mRNA and facilitating “code shifting”, while the nascent viral polyprotein forms a clear interaction with the ribosomal channel. In other words, the interaction between the pseudoknots and the ribosomes causes “code shifting” to occur.
Previously, fluoroquinolones have been reported to inhibit the efficiency of “code shifting” in neovirus and other coronaviruses. This study showed that a molecule called meafloxacin is a better inhibitor of the “code shifting” process. It reduced the titer of neo-coronavirus by 3-4 orders of magnitude and was not toxic to cells.