User:Jeremiah C Hagler/SARS COV 2 RNA Replicase

Overview and Preliminary Questions

RNA-dependent RNA polymerase is a key enzyme in the function of the SARS-CoV-2 coronavirus. This enzyme is unusual in that there are few organisms that utilize RNA-dependent RNA polymerases in their biology. Instead, this tends to be a process that is restricted to certain classes of viruses--including coronaviruses. Because the process of RNA-dependent RNA transcription does not normally occur in human cells, this enzyme is unique to the virus and makes an excellent target for anti-coronavirus drug development.

1. What is transcription?

• 2. What function does the enzyme RNA-dependent RNA polymerase (you can tell by the -ase ending that it is an enzyme) perform?

• 3. In order for coronaviruses to infect a human cell, it needs to liberate its RNA genome into the cytoplasm of the host cell. That RNA can be used to immediately translate a couple of proteins, including the RNA-dependent RNA polymerase. Once the RNA-dependent RNA polymerase is produced, it can go about the business of producing additional transcripts needed to for other viral proteins, and also make copies of the viral genome for packaging into new viral particles. Based on the information given here, do coronaviruses use DNA as a information storage molecule (like the host cell)?

• 4. Thinking about the RNA-dependent RNA polymerase and its function, what molecules would you expect to find associated with this enzyme if this RNA polymerase protein was crystallized “caught in the act”? If you get stuck here, move on the question 5.

The Structure

5. First, before you proceed further, click on the yellow "Load Full" button. Now, looking at the model, can you identify the five subunits (three protein, two nucleic acids)? What are the color of the protein subunits? What are the color of the nucleic acid "subunits"? What type of nucleic acids should be in the active site of this enzyme?

• 6. Because viruses are not affected by antibiotics, researchers look for other drugs to stop viruses. Some of the promising anti-coronavirus drugs interact with RNA-dependent RNA polymerase. Why do you think this protein is a good target for drug development? If you were designing one of these drugs, specifically what kind(s) of interaction(s) would you look for?

• 7. Take a look at this structure. You might notice that there is an additional organic molecule embedded in this structure (the big blobby molecule--it is being shown as a space-filling model rather than a cartoon or stick model like the rest of the molecules in this structure). This molecule is remdesivir. Remdesivir was considered a potential treatment for COVID-19. Take a looklink here for an overview of a study that analyzed the impact of remdesivir on COVID-19 outcomes (just read the abstract). What do you think remdesivir is doing to inhibit the course of SARS-CoV-2 in at least some COVID-19 patients?

References