The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants

作者：Cao, Liu; Li, Yingjun^*; Yang, Sidi; Li, Guanguan; Zhou, Qifan; Sun, Jing; Xu, Tiefeng; Yang, Yang; Liao, Ruyan; Shi, Yongxia; Yang, Yujian; Zhu, Tiaozhen; Huang, Siyao; Ji, Yanxi; Cong, Feng; Luo, Yinzhu; Zhu, Yujun; Luan, Hemi; Zhang, Huan; Chen, Jingdiao; Liu, Xue; Luo, Renru; Liu, Lihong; Wang, Ping; Yu, Yang; Xing, Fan; Ke, Bixia; Zheng, Huanying; Deng, Xiaoling; Zhang, Wenyong; Lin, Chuwen; Shi, Mang; Li, Chun-Mei; Zhang, Yu; Zhang, Lu; Dai, Jun; Lu, Hongzhou

来源：Science Translational Medicine, 2022, 14(661): eabm7621.

DOI：10.1126/scitranslmed.abm7621

• VIRUS

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.

• 单位
  1; 广州医学院; 中山大学