延迟小剂量口服 4′-氟尿嘧啶可抑制致死性疾病动物模型中的致病性阿病毒

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Stephen R. Welch, Jessica R. Spengler, Jonna B. Westover, Kevin W. Bailey, Katherine A. Davies, Virginia Aida-Ficken, Gregory R. Bluemling, Kirsten M. Boardman, Samantha R. Wasson, Shuli Mao, Damien L. Kuiper, Michael W. Hager, Manohar T. Saindane, Meghan K. Andrews, Rebecca E. Krueger, Zachary M. Sticher, Kie Hoon Jung, Payel Chatterjee, Punya Shrivastava-Ranjan, Michael K. Lo, JoAnn D. Coleman-McCray, Teresa E. Sorvillo, Sarah C. Genzer, Florine E. M. Scholte, Jamie A. Kelly, M. Harley Jenks, Laura K. McMullan, César G. Albariño, Joel M. Montgomery, George R. Painter, Michael G. Natchus, Alexander A. Kolykhalov, Brian B. Gowen, Christina F. Spiropoulou, Mike Flint
{"title":"延迟小剂量口服 4′-氟尿嘧啶可抑制致死性疾病动物模型中的致病性阿病毒","authors":"Stephen R. Welch,&nbsp;Jessica R. Spengler,&nbsp;Jonna B. Westover,&nbsp;Kevin W. Bailey,&nbsp;Katherine A. Davies,&nbsp;Virginia Aida-Ficken,&nbsp;Gregory R. Bluemling,&nbsp;Kirsten M. Boardman,&nbsp;Samantha R. Wasson,&nbsp;Shuli Mao,&nbsp;Damien L. Kuiper,&nbsp;Michael W. Hager,&nbsp;Manohar T. Saindane,&nbsp;Meghan K. Andrews,&nbsp;Rebecca E. Krueger,&nbsp;Zachary M. Sticher,&nbsp;Kie Hoon Jung,&nbsp;Payel Chatterjee,&nbsp;Punya Shrivastava-Ranjan,&nbsp;Michael K. Lo,&nbsp;JoAnn D. Coleman-McCray,&nbsp;Teresa E. Sorvillo,&nbsp;Sarah C. Genzer,&nbsp;Florine E. M. Scholte,&nbsp;Jamie A. Kelly,&nbsp;M. Harley Jenks,&nbsp;Laura K. McMullan,&nbsp;César G. Albariño,&nbsp;Joel M. Montgomery,&nbsp;George R. Painter,&nbsp;Michael G. Natchus,&nbsp;Alexander A. Kolykhalov,&nbsp;Brian B. Gowen,&nbsp;Christina F. Spiropoulou,&nbsp;Mike Flint","doi":"10.1126/scitranslmed.ado7034","DOIUrl":null,"url":null,"abstract":"<div >Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 774","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado7034","citationCount":"0","resultStr":"{\"title\":\"Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease\",\"authors\":\"Stephen R. Welch,&nbsp;Jessica R. Spengler,&nbsp;Jonna B. Westover,&nbsp;Kevin W. Bailey,&nbsp;Katherine A. Davies,&nbsp;Virginia Aida-Ficken,&nbsp;Gregory R. Bluemling,&nbsp;Kirsten M. Boardman,&nbsp;Samantha R. Wasson,&nbsp;Shuli Mao,&nbsp;Damien L. Kuiper,&nbsp;Michael W. Hager,&nbsp;Manohar T. Saindane,&nbsp;Meghan K. Andrews,&nbsp;Rebecca E. Krueger,&nbsp;Zachary M. Sticher,&nbsp;Kie Hoon Jung,&nbsp;Payel Chatterjee,&nbsp;Punya Shrivastava-Ranjan,&nbsp;Michael K. Lo,&nbsp;JoAnn D. Coleman-McCray,&nbsp;Teresa E. Sorvillo,&nbsp;Sarah C. Genzer,&nbsp;Florine E. M. Scholte,&nbsp;Jamie A. Kelly,&nbsp;M. Harley Jenks,&nbsp;Laura K. McMullan,&nbsp;César G. Albariño,&nbsp;Joel M. Montgomery,&nbsp;George R. Painter,&nbsp;Michael G. Natchus,&nbsp;Alexander A. Kolykhalov,&nbsp;Brian B. Gowen,&nbsp;Christina F. Spiropoulou,&nbsp;Mike Flint\",\"doi\":\"10.1126/scitranslmed.ado7034\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"16 774\",\"pages\":\"\"},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2024-11-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/scitranslmed.ado7034\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.ado7034\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.ado7034","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

开发广谱抗病毒疗法对于防范新出现和再次出现的病毒爆发和大流行至关重要。诱发出血热的病毒会导致人类的高发病率和高死亡率,并与最近的几次国际疫情爆发有关,但目前还缺乏治疗大多数这些病原体的已获批准的疗法。在这里,我们研究发现,4′-氟尿苷(4′-FlU;EIDD-2749)是一种口服核糖核苷类似物,在细胞培养中对多种出血热病毒具有抗病毒活性,包括尼帕病毒、克里米亚-刚果出血热病毒、正杭病毒和禽流感病毒。我们在豚鼠致死性疾病模型中进行了口服 4′-FlU 对旧世界拉沙病毒(LASV)和新世界胡宁病毒(JUNV)这两种禽流感病毒的临床前体内评估。在这两种致死性疾病豚鼠模型中,4′-FlU 都表现出了良好的药代动力学特征和很高的药效。其他实验证明,即使将 4′-FlU 的剂量降至每公斤 0.5 毫克的低剂量,也能保护受感染的动物。为了证明4′-FlU的临床实用性,我们对感染后期(LASV和JUNV分别为感染后12天或9天)开始的4′-FlU治疗进行了评估。延迟治疗导致临床症状迅速缓解,证明治疗干预的窗口期延长了。这些数据支持使用 4′-FlU 作为一种强效、有效的治疗药物,来对付引起公共卫生关注的高致病性禽流感病毒,其病毒抑制谱表明它是一种广谱的口服抗病毒药物,可用于对付多种病毒病原体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease

Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease
Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信