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4'-氟尿苷是一种口服抗病毒药物，可阻断呼吸道合胞病毒和 SARS-CoV-2 的复制。

4'-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication.

机构信息

Center for Translational Antiviral Research, Georgia State University, Atlanta, GA 30303, USA.

Texas Biomedical Research Institute, San Antonio, TX 78227, USA.

出版信息

Science. 2022 Jan 14;375(6577):161-167. doi: 10.1126/science.abj5508. Epub 2021 Dec 2.

DOI:10.1126/science.abj5508
PMID:34855509
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9206510/
Abstract

The COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and older adults. We describe 4′-fluorouridine (4′-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with high selectivity index in cells and human airway epithelia organoids. Polymerase inhibition within in vitro RNA-dependent RNA polymerase assays established for RSV and SARS-CoV-2 revealed transcriptional stalling after incorporation. Once-daily oral treatment was highly efficacious at 5 milligrams per kilogram (mg/kg) in RSV-infected mice or 20 mg/kg in ferrets infected with different SARS-CoV-2 variants of concern, initiated 24 or 12 hours after infection, respectively. These properties define 4′-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2, and related RNA virus infections.

摘要

COVID-19 大流行凸显了针对呼吸道病毒的广谱治疗药物的迫切需求。呼吸道合胞病毒 (RSV) 对儿科患者和老年人构成重大威胁。我们描述了 4′-氟尿嘧啶核苷 (4′-FlU，EIDD-2749)，这是一种核糖核苷类似物，可抑制 RSV、相关 RNA 病毒和严重急性呼吸系统综合征冠状病毒 2 (SARS-CoV-2)，在细胞和人气道上皮类器官中具有高选择性指数。针对 RSV 和 SARS-CoV-2 建立的体外 RNA 依赖性 RNA 聚合酶测定中的聚合酶抑制作用表明，掺入后会出现转录停滞。在 RSV 感染的小鼠中，每日口服 5 毫克/千克（mg/kg）或在感染不同关注的 SARS-CoV-2 变体的雪貂中，在感染后 24 或 12 小时开始，口服 20 mg/kg，治疗效果非常高。这些特性将 4′-FlU 定义为治疗 RSV、SARS-CoV-2 和相关 RNA 病毒感染的广谱候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/bd0ff877757d/science.abj5508-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/b11c4d8069c9/keyimage.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/1b1d6211ebc4/science.abj5508-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/b7cdf46a5525/science.abj5508-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/6ce6f4672f4c/science.abj5508-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/1658de6634dd/science.abj5508-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/a0f3462a4d98/science.abj5508-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/bd0ff877757d/science.abj5508-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/b11c4d8069c9/keyimage.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/1b1d6211ebc4/science.abj5508-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/b7cdf46a5525/science.abj5508-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/6ce6f4672f4c/science.abj5508-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/1658de6634dd/science.abj5508-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/a0f3462a4d98/science.abj5508-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f017/10026945/bd0ff877757d/science.abj5508-f6.jpg

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