Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 (COVID-19) and continues to be a major health concern worldwide. Strategies to protect individuals at high risk of COVID-19 are critical but are currently a largely unmet need. We evaluated the oral antiviral drug ensitrelvir, which specifically targets the SARS-CoV-2 3CL protease, for its efficacy as a pre-exposure prophylactic treatment. Aged BALB/c mice were subcutaneously treated with various doses of ensitrelvir 24 h prior to a lethal SARS-CoV-2 challenge infection. Mouse body weight changes, survival rates, and viral titers in the lungs were evaluated, and plasma concentrations of ensitrelvir were determined. A single subcutaneous administration of ensitrelvir at 64 mg/kg or greater 24 h prior to SARS-CoV-2 challenge infection significantly protected aged mice against lethality and inhibited body weight loss. Pharmacokinetic analysis of ensitrelvir in the aged mice suggested that plasma concentrations ≥2.99 μg/mL resulted in a significant prophylactic effect against SARS-CoV-2 infection. In the aged mouse prophylaxis model, SARS-CoV-2 titers were suppressed in the lungs of mice treated with ensitrelvir 24 h prior to challenge infection, suggesting that the prophylactic administration of ensitrelvir exerted its prophylactic effect by suppressing viral proliferation. These findings suggest that ensitrelvir is a candidate drug for pre-exposure prophylactic treatment of individuals at high risk of COVID-19.