Prophylactic effect of ensitrelvir in mice infected with SARS-CoV-2
Haruaki Nobori, Keiko Baba, Takayuki Kuroda, Kaoru Baba, Kazumi Matsumoto, Shinpei Yoshida, Ryosuke Watari, Yuki Tachibana, Teruhisa Kato, Keita Fukao
Antiviral Research, doi:10.1016/j.antiviral.2024.105852
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 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.
Effect of prophylactic ensitrelvir on body weight in aged mice infected with SARS-CoV-2 The prophylactic effect of S-217622 against lethal infection with the SARS-CoV-2 MA-P10 strain in mice was evaluated by monitoring body weight loss for 14 d post-challenge infection. A single dose of ensitrelvir administered subcutaneously at 64, 96, or 128 mg/kg 24 h prior to infection significantly suppressed body weight loss due to SARS-CoV-2 infection (Fig. 3 and Supplementary Figure S2 ). A single subcutaneous dose of 32 mg/kg ensitrelvir failed to provide significant prophylactic protection compared to that of vehicle (P ≥ 0.3039). The 64 mg/kg and 96 mg/kg ensitrelvir treatment provided significant protection from weight loss compared to that of vehicle from day 3 through day 7 post-infection (P < 0.05 -P < 0.001). Significant protection was also observed for ensitrelvir doses 128 mg/kg from day 2 through day 7 post-infection (P < 0.001).
Effect of prophylactic ensitrelvir on viral load in the lungs of aged mice infected with SARS-
CoV-2 To evaluate the prophylactic effect of ensitrelvir against lethal infection with the SARS-CoV-2 MA-P10 strain, lung virus titers were measured at 1, 2, 4, and 9 d post-challenge infection. A single prophylactic subcutaneous administration of 64 or 128 mg/kg ensitrelvir 24 h before infection significantly suppressed the lung viral load in mice (Fig. 4 , Supplementary Table S1 ). The lung viral titers peaked at 2 d post-infection and..
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