Further preclinical characterization of molnupiravir against SARS-CoV-2: Antiviral activity determinants and viral genome alteration patterns
[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology
H1-99
0301 basic medicine
0303 health sciences
[SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication
Science (General)
Nucleoside analog
Antiviral drug
HAE
COVID-19
Social sciences (General)
Q1-390
Mutagenesis
Animal model
Research Article
DOI:
10.1016/j.heliyon.2024.e30862
Publication Date:
2024-05-08T16:50:01Z
AUTHORS (17)
ABSTRACT
The SARS-CoV-2 pandemic has highlighted the need for broad-spectrum antiviral drugs to respond promptly to viral emergence. We conducted a preclinical study of molnupiravir (MOV) against SARS-CoV-2 to fully characterise its antiviral properties and mode of action. The antiviral activity of different concentrations of MOV was evaluated ex vivo on human airway epithelium (HAE) and in vivo in a hamster model at three escalating doses (150, 300 and 400 mg/kg/day) according to three different regimens (preventive, pre-emptive and curative). We assessed viral loads and infectious titres at the apical pole of HAE and in hamster lungs, and MOV trough concentration in plasma and lungs. To explore the mode of action of the MOV, the entire genomes of the collected viruses were deep-sequenced. MOV effectively reduced viral titres in HAE and in the lungs of treated animals. Early treatment after infection was a key factor in efficacy, probably associated with high lung concentrations of MOV, suggesting good accumulation in the lung. MOV induced genomic alteration in viral genomes with an increase in the number of minority variants, and predominant G to A transitions. The observed reduction in viral replication and its mechanism of action leading to lethal mutagenesis, supported by clinical trials showing antiviral action in humans, provide a convincing basis for further research as an additional means in the fight against COVID-19 and other RNA viruses.
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CITATIONS (2)
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