Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 14, Issue 661, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abm7621
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Funding
- Shenzhen Science and Technology Program [JSGG20200225150431472, KQTD20180411143323605, JSGG20210901145403012, ZDSYS20190902093215877]
- Shenzhen Bay Laboratory [SZBL2019062801006]
- Guangdong Basic and Applied Basic Research Foundation [2020A1515110361]
- National Key Research and Development Program of China [2021YFC0865100, 2021YFC2301700]
- Key-Area Research and Development Program of Guangdong Province [2021B1111110001]
- Pearl River Talent Plan Innovation and Entrepreneurship Team Project of Guangdong Province [2019ZT08Y464]
- National Natural Science Foundation of China [32041002, 82150206]
- Guangdong Zhujiang Talents Program [2016LJ06Y540]
- National Ten-Thousand Talents Program
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ATV006, an orally bioavailable antiviral drug candidate, showed potent efficacy against various SARS-CoV-2 variants and reduced viral loads and lung damage in mouse models.
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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