Exonuclease and polymerase inhibitors in combination which target two separate COVID-19 enzymes is a potentially useful therapeutic approach
Combining an exonuclease and polymerase inhibitor represents a novel and potentially valuable therapeutic approach to the management of COVID-19 according to a viral cell culture study by researchers from the Center for Genome Technology and Bimolecular Engineering, Columbia University, New York, US.
Within RNA viruses such as COVID-19, there is an RNA-dependent RNA polymerase (RdRp) enzyme and which represents an optimal target due to its crucial role in RNA synthesis. To date, there are many viral RdRp inhibitors which are structurally similar to the natural nucleoside to be recognised by viral polymerase enzyme and be incorporated into the RNA and cause termination of the RNA synthesis. However, one limitation with the use of RdRp inhibitors is that COVID-19 also possesses an exonuclease which leads to the removal of incorporated nucleoside analogues. In other words, the exonuclease effectively works to ‘proof-read’ the assembled RNA and rejects the newly formed strand containing a nucleoside analogue. In practice, this means that such inhibitors are potentially of limited value in the treatment of COVID-19. In fact, this most likely accounts for the limited efficacy of the nucleoside analogue remdesivir in the Solidarity trial with hospitalised COVID-19 patients.
Other research shows that two drugs, daclatasvir, either alone or in combination with sofosbuvir and which are used in the treatment of hepatitis C could be of value in the treatment of COVID-19.
In the present study, the US team examined whether pibrentasvir, ombitasvir (both of which are anti-viral agents used in hepatitis C) and daclatasvir, had anti-exonuclease activity and could therefore act synergistically with RdRp inhibitors for the management of COVID-19.
Exonuclease activity and COVID-19
Using a combination of molecular docking studies and virus replication assays, the US team were able to demonstrate that both pibrentasvir and ombitasvir bound to the endonuclease and were strong inhibitors of the enzyme. With pibrentasvir able to inhibit the endonuclease, the researchers then showed that nucleoside excision of remdesivir did not occur, suggesting that this combination might enable remdesivir to be more effective. In addition further cell culture work also demonstrated a similar and synergistic action when remdesivir was combined with ombitasvir.
Commenting on their findings, the authors suggested that in the presence of COVID-19 endonuclease inhibition with either pibrentasvir or ombitasvir, RdRp inhibitors would be incorporated into COVID-19 RNA during replication and not subsequently excised, thereby substantially enhancing the anti-viral activity of the RdRp inhibitors.
They concluded that based on cell culture study data, the addition of an anti-exonuclease agent, many of which are already available, to the current RdRp inhibitors, would likely be of great benefit by reduces COVID-19 replication.
Wang X et al. Combination of antiviral drugs inhibits SARS-CoV-2 polymerase and exonuclease and demonstrates COVID-19 therapeutic potential in viral cell culture Commun Biol 2022