In a study published in the Journal of Biological Chemistry, Penn State University researchers made strides in understanding the cleavage process of the SARS-CoV-2 virus, shedding light on how its proteins are cleaved during replication. The team, led by Professor Katsuhiko Murakami, utilized cryo-electron microscopy to generate highly detailed 3D visualizations of this process, providing valuable insights into the structural dynamics of the viral polyprotein cleavage.
During replication, the SARS-CoV-2 virus translates its RNA genome into a polyprotein, a long string of connected proteins. The polyprotein is then cleaved into individual proteins by a protease enzyme, and this cleavage process is crucial for viral replication.
The research team focused on understanding the mechanism behind the specific order in which the polyprotein is cleaved. Through cryo-electron microscopy, they saw that the protease, known as Mpro, interacts primarily with the recognition site at the cleavage location, making minimal contact with the rest of the polyprotein. This finding suggests that the structure of the polyprotein itself may determine cleavage order.
Dr. Manju Narwal, the paper's first author, explained that if the protease were solely responsible for determining the order of cleavage, it would be expected to make additional contacts with the polyprotein. However, since this wasn’t observed, the polyprotein's structure likely plays a key role. As each protein is cleaved and separated from the rest of the polyprotein, the next preferred cleavage site becomes accessible, leading to a sequential cleavage process.
Despite the success in visualizing the Mpro-polyprotein complex, the researchers acknowledge that further investigations are needed to fully understand the entire complex and other regions of the polyprotein. By gaining more insights into this critical step in virus replication, scientists hope to develop efficient antiviral drugs that can effectively disrupt the cleavage process.