The adenosine analog prodrug ATV006 is orally bioavailable and has preclinical efficacy against parental SARS-CoV-2 and variants-Reference-Cited by-同舟云学术

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

Published:2022-09-07 Issue:661 Volume:14 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Cao Liu¹^ORCID,Li Yingjun²^ORCID,Yang Sidi¹^ORCID,Li Guanguan²³^ORCID,Zhou Qifan²^ORCID,Sun Jing⁴^ORCID,Xu Tiefeng¹,Yang Yang⁵,Liao Ruyan⁶,Shi Yongxia⁶,Yang Yujian²,Zhu Tiaozhen²,Huang Siyao¹,Ji Yanxi¹,Cong Feng⁷,Luo Yinzhu⁷^ORCID,Zhu Yujun⁷^ORCID,Luan Hemi⁸^ORCID,Zhang Huan⁹,Chen Jingdiao⁹,Liu Xue¹^ORCID,Luo Renru¹,Liu Lihong¹,Wang Ping³,Yu Yang²,Xing Fan¹^ORCID,Ke Bixia⁹,Zheng Huanying⁹^ORCID,Deng Xiaoling⁹,Zhang Wenyong⁸,Lin Chuwen¹,Shi Mang¹^ORCID,Li Chun-Mei¹^ORCID,Zhang Yu⁷^ORCID,Zhang Lu⁶,Dai Jun⁶,Lu Hongzhou⁵^ORCID,Zhao Jincun⁴¹⁰^ORCID,Zhang Xumu²³^ORCID,Guo Deyin¹¹⁰^ORCID

Affiliation:

1. Centre for Infection and Immunity Studies (CIIS), School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong, 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, Guangdong, China.

3. Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518118, Guangdong, 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, Guangdong, 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, Guangdong, China.

6. Guangzhou Customs District Technology Center, Guangzhou 510623, Guangdong, China.

7. Guangdong Province Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou 510663, Guangdong, China.

8. School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.

9. Center for Disease Control and Prevention of Guangdong Province, Guangzhou 511430, Guangdong, China.

10. Guangzhou Laboratory, Bio Island, Guangzhou 510320, Guangdong, China.

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. 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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