Summary by: Arooba Ahmed (CC '23)
Dr. Ju reports on evaluating mutant analogos and inhibitors of COVID polymerases. Thus far, they have experimentally identified mutant 5 analogs. Currently, 4 are FTF approved drugs of other viral conditions. These molecules or similarly structured ones can be potential therapeutics for COVID-19.
The COVID-19 virus is simpler than the flu in that it consists of a single piece of positive RNA genome, which then uses an RNA dependent RNA polymerase in the host cell to take over. This type of virus is well defined in the human host and is differentiable as we don't use R dependent RNA polymerases to replicate the genome.
Remdesivir is an inhibitor of the COVID- polymerase that is currently in clinical trial as a potential therapy. Remdesivir interferes with the action of viral RNA-dependent RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production, eradicating the virus.
Dr. Ju’s lab specializes in designing syntheses of structure activity of molecules, nucleotide analogs, and polymerase substrates. In this particular project, they focus on polymerase terminators (which are a section of the genome that marks the end of a particular gene, and eventually allows the release of RNA from transcription machinery). Looking at Remdesivir, the basic structure of this molecule has been altered with key molecular groups in order to find a structure that inhibits the polymers of the SARS.
Other forms of this molecule exist as well, such as sofosbuvir, which has been approved for Hepatitis C. As a prodrug nucleotide analog, Sofosbuvir is metabolized into its active form as the antiviral agent GS-461203. Hepatitis C has a similar replication structure as the coronavirus because they both contain a positive strand of RNA genome. Because of this similarity, they also want to see whether this drug can inhibit the new coronavirus polymerase. They found that the inhibitors of polymerase have less steric hindrance (slowing of chemical reactions due to non-bonding chemical interactions).
In this project, they designed a simple template and primer based on the coronavirus genome and completed mass spectrometry analysis to determine if the molecule is an inhibitor of the polymerase. They used the polymerase from the previous SARS virus, which could establish feasibility that the new coronavirus polymerase can use this molecule as a terminator since they are 98% similar. They selected a group of molecules from the approved drugs and, in a simple assay, found they are all terminators of the polymerase. Next, they combined two drugs, TFV and Embicitimine (two components of the FDA approved drugs of HIV which act as chemical vaccines for HIV prevention). They found that the triphosphate form of both also terminate coronavirus. In total, they identified 5 molecules as polymerase terminators of new coronavirus.