Broad-spectrum antiviral inhibits novel coronavirus
There was a dose-dependent reduction in novel coronavirus infections in human airway epithelial cell cultures
- Broad-spectrum antivirals for emerging zoonotic infections become particularly important when specific interventions do not yet exist.
- Researchers have found that a ribonucleoside analogue (beta-D-N4-hydroxycytidine or NHC) that has previously shown to be effective against influenza and Ebola is also potent against coronaviruses, including the novel coronavirus that is currently causing the pandemic.
- The drug was found to be effective in both cell lines and primary human airway epithelial cultures against SARS, MERS and SARS-CoV-2.
- It was also effective against three closely-related bat coronaviruses that were capable of replicating in human cells without undergoing any adaptation, suggesting potential direct transmission from bats to humans.
In vitro analysis
- The NHC drug is highly active against all three coronaviruses — 2002 SARS, MERS and the novel coronavirus.
- While it was not toxic to human cells, there was a dose-dependent reduction in SARS, MERS and novel coronavirus infectious virus production in human airway epithelial cell cultures.
- The antiviral activity of NHC arises from increased mutation rate in viral genomic RNA.
- In the case of MERS, treatment with 1 microMolar of NHC resulted in three-fold increase in error rate and 138-fold decrease in virus titer.
- When the amount of NHC used was increased to 10 microMolar, the error rate increased sixfold and virus titer reduction increased 26,000-fold.
- Explaining the process that leads to increased mutation rates, the authors say that NHC gets incorporated during RNA synthesis and then subsequently misread leading to enhanced mutation.
- Encouraged by these results, the researchers tested an orally bioavailable prodrug of NHC designed for improved oral bioavailability in humans and non-human primates and better pharmacokinetics.
- The prodrug was tested in vitro using the 2002 SARS coronavirus.
- Lung haemorrhage was significantly reduced and there was a dose-dependent reduction in lung titer of SARS coronavirus.
- The prodrug given as a prophylactic was “robustly antiviral” and was able to prevent SARS coronavirus replication and disease.
- As in the case of the 2002 SARS coronavirus, in genetically modified mice, the prodrug protected from significant weight loss and lung haemorrhage due to MERS.
- Viral replication was not seen at all prophylactic doses (50, 150 and 500 mg per kg).
- But only treatment initiated before 12 after MERS infection prevented body weight loss.