Title | Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses |
Author | |
Corresponding Author | Li,Yingjun |
Publication Years | 2023-03-05
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DOI | |
Source Title | |
ISSN | 0223-5234
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EISSN | 1768-3254
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Volume | 249 |
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]
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WOS Research Area | Pharmacology & Pharmacy
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WOS Subject | Chemistry, Medicinal
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WOS Accession No | WOS:000934155100001
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Publisher | |
ESI Research Field | CHEMISTRY
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Scopus EID | 2-s2.0-85146905573
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Data Source | Scopus
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Citation statistics |
Cited Times [WOS]:0
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Document Type | Journal Article |
Identifier | http://kc.sustech.edu.cn/handle/2SGJ60CL/442618 |
Department | Department 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 Affilication | Department of Chemistry; Academy for Advanced Interdisciplinary Studies; College of Science |
Corresponding Author Affilication | Department of Chemistry; Academy for Advanced Interdisciplinary Studies; College of Science |
First Author's First Affilication | Department 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.
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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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