Study on molnupiravir precursor NHC antiviral activity against SARS-CoV-2 mutants of concern

The 2019 coronavirus disease (COVID-19) pandemic was caused by a new coronavirus, Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2). As a result of the continued efforts of scientists, we now have several vaccines to combat the pandemic.

In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) recently licensed the antiviral drug molnupiravir for use in patients with mild to moderate COVID-19. The drug is known to be most effective when started early, but the exact window in which the drug can be used remains elusive.

In a new study bioRxiv* Preprint server, scientists aimed to determine the response of molnupiravir parental drug (NHC) to various SARS-CoV-2 variant of concern (VoC). They also sought to establish a treatment window in the human lung cell model.

Molnupiravir in the treatment of SARS-CoV-2 infection

Molnupiravir is an antiviral prodrug that was first developed to combat the influenza virus. Currently in clinical trials in humans for the treatment of COVID-19.

Some preliminary results show that the drug reduced the risk of hospitalization or death by 50%. In addition, it was noted that efficacy did not change depending on the timing of the onset of symptoms, the underlying risk factors, or certain variants.

Scientists have observed in a ferret model that treatment of SARS-CoV-2 infection with molnupiravir resulted in a reduction in the upper respiratory tract. Viral load It also prevented transmission between animals.

The results were also strong in the mouse model, and the combination of molnupiravir and favipiravir was also found to be effective in the hamster model. However, most of these studies used early variants of the virus rather than recent VOCs.

The parent drug of molnupiravir is known as NHC or β-D-N4-hydroxycytidine. In two independent studies, Effectiveness of NHC (for Alpha and Beta variants of Vero E6 and Calu3 cells) has been demonstrated. However, its efficacy in inhibiting viral replication to the delta variant has not yet been documented.

In the current study, scientists hoped to fill this gap in the literature and used the human lung epithelial cell model (hACE2-A549 cells) for this purpose.

Main survey results

In this study, researchers performed a dose-response assay (in parallel) to determine the NHC’s IC50 (the concentration of drug 32 required to inhibit 50% viral titer). This was done for various variants of SARS-CoV-2.

Human ACE-2A549 cells were treated with NHC at various times, either before, during, or after infection with SARS-CoV-2.

The active metabolite of molnupiravir is β-D-N4-hydroxycytidine (NHC). In this study, researchers found that β-D-N4-hydroxycytidine (NHC) was applied to four mutants of the human lung cell line SARS-CoV-2 (strain B, alpha, beta, and delta). It has been shown to have similar activity.

The IC50 was found to be in the range 0.04 to 0.16 µM. Scientists have also shown that the drug’s activity began to decline 48 hours after infection.

The results obtained from this analysis support clinical data showing the inhibitory effect of molnupiravir on SARS-CoV-2.

Molnupiravir mimics the naturally occurring nucleosides and causes error catastrophes during viral replication in the host. For this reason, it is expected to work against all variants of the virus.

This last claim was tested and proven in four variants, as mentioned above. The data are consistent with the results of the MOVe-In trial, which prematurely discontinued the use of molnupiravir in hospitalized patients because it was considered unlikely to have a statistically significant effect. It also supports the decision to approve the drug for use in mild to moderate cases.

Limits In vitro system

In vitro Studies have many limitations compared to live models of infection. The use of molnupiravir in a Syrian hamster model infected with SARS-CoV-2 reduced viral load and reduced lung lesions. However, it was observed that treatment administered 12 hours after infection was effective, but not 24 hours after infection. Further research is needed to narrow down the ideal treatment period for drugs in humans with mild to moderate disease.

Conclusion

The advantage of molnupiravir over remdesivir is that it can be administered orally. However, it is important to note that antiviral resistance can develop rapidly, as observed with the influenza antiviral agent Tamiflu.

An overall analysis of the potential of SARSCoV-2 to develop resistance is needed. Researchers argue that treatment with molnupiravir may be most effective when used in combination with other treatments, such as those that target different parts of the viral life cycle. I am. This principle has been successfully applied to the treatment of HIV.

*Important Notices

bioRxiv Publish preliminary scientific reports that should not be considered definitive as they have not been peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information.