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

• DOI: 10.1126/scitranslmed.abm7621
• Publication Date: 2022-05-17T13:57:48Z
• Authors: Liu Cao; Yingjun Li; Sidi Yang; Guanguan Li; Qifan Zhou; Jing Sun; Tiefeng Xu; Yang Yang; Ruyan Liao; Yongxia Shi; Yujian Yang; Tiaozhen Zhu; Siyao Huang; Yanxi Ji; Feng Cong; Yinzhu Luo; Yujun Zhu; Hemi Luan; Huan Zhang; Jingdiao Chen; Xue Liu; Renru Luo; Lihong Liu; Ping Wang; Yang Yu; Fan Xing; Bixia Ke; Huanying Zheng; Xiaoling Deng; Wenyong Zhang; Chuwen Lin; Mang Shi; Chun-Mei Li; Yu Zhang; Lu Zhang; Jun Dai; Hongzhou Lu; Jincun Zhao; Xumu Zhang; Deyin Guo
• Keywords: 0301 basic medicine; Adenosine; SARS-CoV-2; Antiviral Agents; Adenosine Monophosphate; Rats; COVID-19 Drug Treatment; 3. Good health; Mice; 03 medical and health sciences; Animals; Prodrugs; Research Articles

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.