Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Because of the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOCs), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously, we showed that the parent nucleoside of remdesivir, GS-441524, has potent anti-SARS-CoV-2 activity. Here, we report that esterification of the 5′-hydroxyl moieties of GS-441524 markedly improved antiviral potency. This 5′-hydroxyl-isobutyryl prodrug, ATV006, demonstrated excellent oral bioavailability in rats and cynomolgus monkeys and exhibited potent antiviral efficacy against different SARS-CoV-2 VOCs in vitro and in three mouse models. Oral administration of ATV006 reduced viral loads and alleviated lung damage when administered prophylactically and therapeutically to K18-hACE2 mice challenged with the Delta variant of SARS-CoV-2. These data indicate that ATV006 represents a promising oral antiviral drug candidate for SARS-CoV-2.
【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, Efficacy, coronavirus, vaccination, pandemic, VoC, variants of concern, Remdesivir, in vitro, delta variant, virus, antiviral drug, SARS-CoV-2 transmission, VOCs, GS-441524, antiviral efficacy, K18-hACE2 mice, Mouse models, Anti-SARS-CoV-2 Activity, lung damage, oral administration, acute respiratory syndrome, parent nucleoside, driving, antiviral potency, Administered, oral bioavailability, exhibited, demonstrated, prophylactically, reduced viral load, 【제목키워드】 SARS-CoV-2, Efficacy, variant, parental,