Centre for Infection and Immunity Studies (CIIS), School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
Sci Transl Med. 2022 Sep 7;14(661):eabm7621. doi: 10.1126/scitranslmed.abm7621.
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.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是导致当前 2019 年冠状病毒病（COVID-19）大流行的病毒，它仍在迅速演变。由于疫苗在预防 SARS-CoV-2 传播方面的效果有限，以及不断出现令人关注的变异株（VOCs），因此迫切需要口服生物利用度高且广泛有效的抗病毒药物。此前，我们已经表明，瑞德西韦的母核核苷 GS-441524 具有很强的抗 SARS-CoV-2 活性。在这里，我们报告说，GS-441524 的 5'-羟基酯化显著提高了抗病毒效力。这种 5'-羟基异丁酰基前药 ATV006 在大鼠和食蟹猴中表现出优异的口服生物利用度，并在体外和三种小鼠模型中对不同的 SARS-CoV-2 VOC 表现出强大的抗病毒功效。当预防性和治疗性地给予 K18-hACE2 小鼠感染 SARS-CoV-2 的 Delta 变异株时，口服给予 ATV006 可降低病毒载量并减轻肺部损伤。这些数据表明，ATV006 是一种很有前途的针对 SARS-CoV-2 的口服抗病毒药物候选物。
