Antiviral activity of molnupiravir precursor NHC against Variants of Concern (VOCs) and its therapeutic window in a human lung cell model

Background: The UK Medicines and Regulatory Healthcare Agency (MHRA) have recently licensed the anti-viral drug, molnupiravir, for use in patients with mild-moderate COVID-19 disease with one or more risk factors for serious illness. Treatment with anti-viral drugs is best initiated early to prevent progression to severe disease, although the therapeutic window for intervention has not yet been fully defined. Objectives: This study aimed to determine the activity of the molnupiravir parent drug (NHC) to different SARS-CoV-2 Variants of Concern (VoCs), and to establish the therapeutic window in human lung cell model. Methods: Dose response assays were performed in parallel to determine the IC50 (the concentration of drug required to inhibit virus titre by 50%) of NHC against different variants. Human ACE-2 A549 cells were treated with NHC at different time points either before, during or after infection with SARS-CoV-2. Results: Here we demonstrate that β-D-N4-hydroxycytidine (NHC), the active metabolite of molnupiravir, has equivalent activity against four variants of SARS-CoV-2 in a human lung cell line ranging 0.04-0.16μM IC50. Furthermore, we demonstrate that activity of the drug begins to drop after 48 hours post-infection. Conclusions: One of the main advantages of molnupiravir is that it can be administered orally, and thus given to patients in an out-patient setting. These results support giving the drug early on after diagnosis or even in prophylaxis for individuals with high risk of developing severe disease.