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

Cao，Liu1; Li，Yingjun2; Yang，Sidi1; Li，Guanguan2,3; Zhou，Qifan2; Sun，Jing4; Xu，Tiefeng1; Yang，Yang5; Liao，Ruyan6; Shi，Yongxia6; Yang，Yujian2; Zhu，Tiaozhen2; Huang，Siyao1; Ji，Yanxi1; Cong，Feng7; Luo，Yinzhu7; Zhu，Yujun7; Luan，Hemi8; Zhang，Huan9; Chen，Jingdiao9; Liu，Xue1; Luo，Renru1; Liu，Lihong1; Wang，Ping3; Yu，Yang2; Xing，Fan1; Ke，Bixia9; Zheng，Huanying9; Deng，Xiaoling9; Zhang，Wenyong8; Lin，Chuwen1; Shi，Mang1; Li，Chun Mei1; Zhang，Yu7; Zhang，Lu6; Dai，Jun6; Lu，Hongzhou5; Zhao，Jincun4,10; Zhang，Xumu2,3; Guo，Deyin1,10

2022-09-07

10.1126/scitranslmed.abm7621

Science translational medicine   Impact Factor & Quartile

1946-6242

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.

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1.Centre for Infection and Immunity Studies (CIIS),School of Medicine,Shenzhen,Shenzhen Campus of Sun Yat-sen University,518107,China
2.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,China
3.Medi-X Pingshan,Southern University of Science and Technology,Shenzhen,518118,China
4.State Key Laboratory of Respiratory Disease,National Clinical Research Center for Respiratory Disease,Guangzhou Institute of Respiratory Health,First Affiliated Hospital of Guangzhou Medical University,Guangzhou,510182,China
5.Shenzhen Key Laboratory of Pathogen and Immunity,National Clinical Research Center for infectious disease,State Key Discipline of Infectious Disease,Shenzhen Third People's Hospital,Second Hospital Affiliated to Southern University of Science and Technology,Shenzhen,518112,China
6.Guangzhou Customs District Technology Center,Guangzhou,510623,China
7.Guangdong Province Key Laboratory of Laboratory Animals,Guangdong Laboratory Animals Monitoring Institute,Guangzhou,510663,China
8.School of Medicine,Southern University of Science and Technology,Shenzhen,518055,China
9.Center for Disease Control and Prevention of Guangdong Province,Guangzhou,511430,China
10.Guangzhou Laboratory,Bio Island,Guangzhou,510320,China

Cao，Liu,Li，Yingjun,Yang，Sidi,et al. The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants[J]. Science translational medicine,2022,14(661).

Cao，Liu.,Li，Yingjun.,Yang，Sidi.,Li，Guanguan.,Zhou，Qifan.,...&Guo，Deyin.(2022).The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants.Science translational medicine,14(661).

Cao，Liu,et al."The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants".Science translational medicine 14.661(2022).