tetano
Editor, Senior Moderator
Sci Transl Med
. 2022 May 17;eabm7621.
doi: 10.1126/scitranslmed.abm7621. Online ahead of print.
The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants
Liu Cao[SUP] #[/SUP][SUP] 1 [/SUP], Yingjun Li[SUP] #[/SUP][SUP] 2 [/SUP], Sidi Yang[SUP] #[/SUP][SUP] 1 [/SUP], Guanguan Li[SUP] #[/SUP][SUP] 2 3 [/SUP], Qifan Zhou[SUP] #[/SUP][SUP] 2 [/SUP], Jing Sun[SUP] #[/SUP][SUP] 4 [/SUP], Tiefeng Xu[SUP] 1 [/SUP], Yang Yang[SUP] 5 [/SUP], Ruyan Liao[SUP] 6 [/SUP], Yongxia Shi[SUP] 6 [/SUP], Yujian Yang[SUP] 2 [/SUP], Tiaozhen Zhu[SUP] 2 [/SUP], Siyao Huang[SUP] 1 [/SUP], Yanxi Ji[SUP] 1 [/SUP], Feng Cong[SUP] 7 [/SUP], Yinzhu Luo[SUP] 7 [/SUP], Yujun Zhu[SUP] 7 [/SUP], Hemi Luan[SUP] 8 [/SUP], Huan Zhang[SUP] 9 [/SUP], Jingdiao Chen[SUP] 9 [/SUP], Xue Liu[SUP] 1 [/SUP], Renru Luo[SUP] 1 [/SUP], Lihong Liu[SUP] 1 [/SUP], Ping Wang[SUP] 3 [/SUP], Yang Yu[SUP] 2 [/SUP], Fan Xing[SUP] 1 [/SUP], Bixia Ke[SUP] 9 [/SUP], Huanying Zheng[SUP] 9 [/SUP], Xiaoling Deng[SUP] 9 [/SUP], Wenyong Zhang[SUP] 8 [/SUP], Chuwen Lin[SUP] 1 [/SUP], Mang Shi[SUP] 1 [/SUP], Chun-Mei Li[SUP] 1 [/SUP], Yu Zhang[SUP] 6 [/SUP], Lu Zhang[SUP] 5 [/SUP], Jun Dai[SUP] 6 [/SUP], Hongzhou Lu[SUP] 5 [/SUP], Jincun Zhao[SUP] 4 10 [/SUP], Xumu Zhang[SUP] 2 3 [/SUP], Deyin Guo[SUP] 1 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that the parent nucleoside of remdesivir, GS-441524, possesses potent anti-SARS-CoV-2 activity. Herein, 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.
. 2022 May 17;eabm7621.
doi: 10.1126/scitranslmed.abm7621. Online ahead of print.
The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants
Liu Cao[SUP] #[/SUP][SUP] 1 [/SUP], Yingjun Li[SUP] #[/SUP][SUP] 2 [/SUP], Sidi Yang[SUP] #[/SUP][SUP] 1 [/SUP], Guanguan Li[SUP] #[/SUP][SUP] 2 3 [/SUP], Qifan Zhou[SUP] #[/SUP][SUP] 2 [/SUP], Jing Sun[SUP] #[/SUP][SUP] 4 [/SUP], Tiefeng Xu[SUP] 1 [/SUP], Yang Yang[SUP] 5 [/SUP], Ruyan Liao[SUP] 6 [/SUP], Yongxia Shi[SUP] 6 [/SUP], Yujian Yang[SUP] 2 [/SUP], Tiaozhen Zhu[SUP] 2 [/SUP], Siyao Huang[SUP] 1 [/SUP], Yanxi Ji[SUP] 1 [/SUP], Feng Cong[SUP] 7 [/SUP], Yinzhu Luo[SUP] 7 [/SUP], Yujun Zhu[SUP] 7 [/SUP], Hemi Luan[SUP] 8 [/SUP], Huan Zhang[SUP] 9 [/SUP], Jingdiao Chen[SUP] 9 [/SUP], Xue Liu[SUP] 1 [/SUP], Renru Luo[SUP] 1 [/SUP], Lihong Liu[SUP] 1 [/SUP], Ping Wang[SUP] 3 [/SUP], Yang Yu[SUP] 2 [/SUP], Fan Xing[SUP] 1 [/SUP], Bixia Ke[SUP] 9 [/SUP], Huanying Zheng[SUP] 9 [/SUP], Xiaoling Deng[SUP] 9 [/SUP], Wenyong Zhang[SUP] 8 [/SUP], Chuwen Lin[SUP] 1 [/SUP], Mang Shi[SUP] 1 [/SUP], Chun-Mei Li[SUP] 1 [/SUP], Yu Zhang[SUP] 6 [/SUP], Lu Zhang[SUP] 5 [/SUP], Jun Dai[SUP] 6 [/SUP], Hongzhou Lu[SUP] 5 [/SUP], Jincun Zhao[SUP] 4 10 [/SUP], Xumu Zhang[SUP] 2 3 [/SUP], Deyin Guo[SUP] 1 [/SUP]
Affiliations
- PMID: 35579533
- DOI: 10.1126/scitranslmed.abm7621
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus driving the ongoing coronavirus disease 2019 (COVID-19) pandemic, continues to rapidly evolve. Due to the limited efficacy of vaccination in prevention of SARS-CoV-2 transmission and continuous emergence of variants of concern (VOC), orally bioavailable and broadly efficacious antiviral drugs are urgently needed. Previously we showed that the parent nucleoside of remdesivir, GS-441524, possesses potent anti-SARS-CoV-2 activity. Herein, 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.