南方科技大学知识苑(SUSTech KC): Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses

题名	Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses
作者	Zhou，Qifan1 ; Luo，Yinzhu 2; Zhu，Yujun 2; Chen，Qishu1 ; Qiu，Jingfei 1; Cong，Feng 2; Li，Yingjun1,3 ; Zhang，Xumu1
通讯作者	Li，Yingjun
发表日期	2023-03-05
DOI	10.1016/j.ejmech.2023.115113
发表期刊	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 影响因子和分区
ISSN	0223-5234
EISSN	1768-3254
卷号	249
摘要	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.
关键词	Coronavirus Ibuprofen NSAIDs Nucleotide Oral antiviral agent RNA dependent RNA polymerase
相关链接	[Scopus记录]
收录类别	SCI ; IC
语种	英语
学校署名	第一 ; 通讯
资助项目	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研究方向	Pharmacology & Pharmacy
WOS类目	Chemistry, Medicinal
WOS记录号	WOS:000934155100001
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
ESI学科分类	CHEMISTRY
Scopus记录号	2-s2.0-85146905573
来源库	Scopus
引用统计	被引频次[WOS]：6
成果类型	期刊论文
条目标识符	http://sustech.caswiz.com/handle/2SGJ60CL/442618
专题	理学院_化学系理学院前沿与交叉科学研究院
作者单位	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
第一作者单位	化学系; 前沿与交叉科学研究院; 理学院
通讯作者单位	化学系; 前沿与交叉科学研究院; 理学院
第一作者的第一单位	化学系; 前沿与交叉科学研究院; 理学院
推荐引用方式 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).