Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection.
Pyrimidine biosynthesis inhibitors synergize with nucleoside analogs to block SARS-CoV-2 infection.
复制标题
嘧啶生物合成抑制剂与核苷类似物协同作用，阻断 SARS-CoV-2 感染。
DOI：
10.1101/2021.06.24.449811
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Fer
中科院分区：
文献类型：
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作者：
Schultz,DavidC;Johnson,RobertM;Ayyanathan,Kasirajan;Miller,Jesse;Whig,Kanupriya;Kamalia,Brinda;Dittmar,Mark;Weston,Stuart;Hammond,HollyL;Dillen,Carly;Castellana,Lauren;Lee,JaeSeung;Li,Minghua;Lee,Emily;Constant,Samuel;Fer
持续的 COVID-19 大流行凸显了治疗病毒感染的批准药物的缺乏，FDA 批准的针对人类病毒病原体的药物仅有约 90 种。为了确定可以阻止 SARS-CoV-2 复制的药物，正在进行广泛的药物筛选，以重新利用已批准的药物。在这里，我们利用人类呼吸道细胞中的活病毒感染筛选了约 18,000 种药物的抗病毒活性。剂量反应研究验证了 122 种药物具有抗病毒活性和针对 SARS-CoV-2 的选择性。这些候选药物中有 16 种核苷类似物，是临床使用的最大类别的抗病毒药物。其中包括批准用于治疗 COVID-19 的抗病毒药物 Remdesivir 和正在进行临床试验的核苷 Molnupirivir。 RNA病毒依赖于宿主提供的大量三磷酸核苷来有效复制，我们鉴定了一组宿主核苷生物合成抑制剂作为抗病毒药物，我们发现将嘧啶生物合成抑制剂与抗病毒核苷类似物相结合可在体外和体内协同抑制SARS-CoV-2感染，这表明了一条临床前进之路。
The ongoing COVID-19 pandemic has highlighted the dearth of approved drugs to treat viral infections, with only ∼90 FDA approved drugs against human viral pathogens. To identify drugs that can block SARS-CoV-2 replication, extensive drug screening to repurpose approved drugs is underway. Here, we screened ∼18,000 drugs for antiviral activity using live virus infection in human respiratory cells. Dose-response studies validate 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Amongst these drug candidates are 16 nucleoside analogs, the largest category of clinically used antivirals. This included the antiviral Remdesivir approved for use in COVID-19, and the nucleoside Molnupirivir, which is undergoing clinical trials. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral, and we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogs synergistically inhibits SARS-CoV-2 infection in vitro and in vivo suggesting a clinical path forward.