中文版 | English
Title

Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses

Author
Corresponding AuthorLi,Yingjun
Publication Years
2023-03-05
DOI
Source Title
ISSN
0223-5234
EISSN
1768-3254
Volume249
Abstract
Coronaviruses (CoVs) infect a broad range of hosts, including humans and various animals, with a tendency to cross the species barrier, causing severe harm to human society and fostering the need for effective anti-coronaviral drugs. GS-441524 is a broad-spectrum antiviral nucleoside with potent anti-CoVs activities. However, its application is limited by poor oral bioavailability. Herein, we designed and synthesized several conjugates via covalently binding NSAIDs to 5′-OH of GS-441524 through ester bonds. The ibuprofen conjugate, ATV041, exhibited potent in vitro anti-coronaviral efficacy against four zoonotic coronaviruses in the alpha- and beta-genera. Oral-dosed ATV041 resulted in favorable bioavailability and rapid tissue distribution of GS-441524 and ibuprofen. In MHV-A59 infected mice, ATV041 dose-dependently decreased viral RNA replication and significantly reduced the proinflammatory cytokines in the liver and the lung at 3 dpi. As a result, the MHV-A59-induced lung and liver inflammatory injury was significantly alleviated. Taken together, this work provides a novel drug conjugate strategy to improve oral PK and offers a potent anti-coronaviral lead compound for further studies.
Keywords
URL[Source Record]
Indexed By
Language
English
SUSTech Authorship
First ; Corresponding
Funding Project
National Natural Science Foundation of China[82150206] ; National Natural Science Foundation of China Youth Program["32000360","82204194"] ; Shenzhen Sci- ence and Technology Program["JSGG20210901145403012","JCYJ20220530113609021"] ; Science and Technology Program of Guangzhou, China[202102080304] ; Guangdong Education department[2022KTSCX107]
WOS Research Area
Pharmacology & Pharmacy
WOS Subject
Chemistry, Medicinal
WOS Accession No
WOS:000934155100001
Publisher
ESI Research Field
CHEMISTRY
Scopus EID
2-s2.0-85146905573
Data Source
Scopus
Citation statistics
Cited Times [WOS]:0
Document TypeJournal Article
Identifierhttp://kc.sustech.edu.cn/handle/2SGJ60CL/442618
DepartmentDepartment of Chemistry
理学院
前沿与交叉科学研究院
Affiliation
1.Department of Chemistry,College of Science,Academy for Advanced Interdisciplinary Studies and Medi-X Pingshan,Southern University of Science and Technology,Shenzhen,Guangdong,518000,China
2.Guangdong Province Key Laboratory of Laboratory Animals,Guangdong Laboratory Animals Monitoring Institute,Guangzhou,Guangdong,510663,China
3.State Key Laboratory of Chemical Oncogenomics,Tsinghua Shenzhen International Graduate School,Shenzhen,518055,China
First Author AffilicationDepartment of Chemistry;  Academy for Advanced Interdisciplinary Studies;  College of Science
Corresponding Author AffilicationDepartment of Chemistry;  Academy for Advanced Interdisciplinary Studies;  College of Science
First Author's First AffilicationDepartment of Chemistry;  Academy for Advanced Interdisciplinary Studies;  College of Science
Recommended Citation
GB/T 7714
Zhou,Qifan,Luo,Yinzhu,Zhu,Yujun,et al. Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2023,249.
APA
Zhou,Qifan.,Luo,Yinzhu.,Zhu,Yujun.,Chen,Qishu.,Qiu,Jingfei.,...&Zhang,Xumu.(2023).Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,249.
MLA
Zhou,Qifan,et al."Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 249(2023).
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