Combining an exonuclease and polymerase inhibitor which target two separate COVID-19 enzymes is a potentially useful treatment approach
Adding an exonuclease inhibitor to a polymerase inhibitor is a novel and potentially useful therapeutic approach for the management of COVID-19. This was according to a viral cell culture study by researchers from the Center for Genome Technology and Bimolecular Engineering, Columbia University, New York, US.
COVID-19 is an RNA virus and possesses an RNA-dependent RNA polymerase (RdRp) enzyme which represents an optimal target due to its crucial role in RNA synthesis. To date, there are several viral RdRp inhibitors which are structurally similar to the natural nucleosides recognised by a viral polymerase enzyme and incorporated into the RNA, leading to termination of the RNA synthesis. However, one limitation with the use of RdRp inhibitors is that COVID-19 also possesses an exonuclease enzyme which leads to the removal of incorporated synthetic nucleoside analogues. In other words, the exonuclease effectively works to ‘proof-read’ the assembled RNA and rejects a newly formed strand which contains the 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.
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 might 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