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

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

  • Sci Transl Med. 2022 Sep 7;14(661):eabm7621. doi: 10.1126/scitranslmed.abm7621.
Liu Cao 1,  Yingjun Li 2,  Sidi Yang 1,  Guanguan Li 2 3,  Qifan Zhou 2,  Jing Sun 4,  Tiefeng Xu 1,  Yang Yang 5,  Ruyan Liao 6,  Yongxia Shi 6,  Yujian Yang 2,  Tiaozhen Zhu 2,  Siyao Huang 1,  Yanxi Ji 1,  Feng Cong 7,  Yinzhu Luo 7,  Yujun Zhu 7,  Hemi Luan 8,  Huan Zhang 9,  Jingdiao Chen 9,  Xue Liu 1,  Renru Luo 1,  Lihong Liu 1,  Ping Wang 3,  Yang Yu 2,  Fan Xing 1,  Bixia Ke 9,  Huanying Zheng 9,  Xiaoling Deng 9,  Wenyong Zhang 8,  Chuwen Lin 1,  Mang Shi 1,  Chun-Mei Li 1,  Yu Zhang 7,  Lu Zhang 6,  Jun Dai 6,  Hongzhou Lu 5,  Jincun Zhao 4 10,  Xumu Zhang 2 3,  Deyin Guo 1 10
Affiliations

Affiliations

  • 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.
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. 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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