The adenosine analogue prodrug ATV006 is orally bioavailable and has potent preclinical efficacy against SARS-CoV-2 and its variants

Cao, Liu; Li, Yingjun; Yang, Sidi; Li, Guanguan; Zhou, Qifan; Sun, Jing; Xu, Tiefeng; Yang, Yujian; Zhu, Tiaozhen; Huang, Siyao; Ji, Yanxi; Cong, Feng; Luo, Yinzhu; Zhu, Yujun; Luan, Hemi; Zhang, Huan; Chen, Jingdiao; Liu, Xue; Wang, Ping; Yu, Yang; Xing, Fan; Ke, Bixia; Zheng, Huanying; Deng, Xiaoling; Zhang, Wenyong; Li, Chun-Mei; Zhang, Yu; Zhao, Jincun; Zhang, Xumu; Guo, Deyin

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the COVID-19 pandemic, is rapidly evolving. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), including the currently most prevalent Delta variant, orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that adenosine analogue 69-0 (also known as GS-441524), possesses potent anti-SARS-CoV-2 activity. Herein, we report that esterification of the 5’-hydroxyl moieties of 69-0 markedly improved the antiviral potency. The 5’-hydroxyl-isobutyryl prodrug, ATV006, showed excellent oral bioavailability in rats and cynomolgus monkeys and potent antiviral efficacy against different VOCs of SARS-CoV-2 in cell culture and three mouse models. Oral administration of ATV006 significantly reduced viral loads, alleviated lung damage and rescued mice from death in the K18-hACE2 mouse model challenged with the Delta variant. Moreover, ATV006 showed broad antiviral efficacy against different mammal-infecting coronaviruses. These indicate that ATV006 represents a promising oral drug candidate against SARS-CoV-2 VOCs and other coronaviruses.