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

Zhou，Qifan1; Luo，Yinzhu2; Zhu，Yujun2; Chen，Qishu1; Qiu，Jingfei1; Cong，Feng2; Li，Yingjun1,3; Zhang，Xumu1

2023-03-05

10.1016/j.ejmech.2023.115113

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY   Impact Factor & Quartile

0223-5234

1768-3254

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.

Coronavirus Ibuprofen NSAIDs Nucleotide Oral antiviral agent RNA dependent RNA polymerase

SCI

English

First ; Corresponding

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]

Pharmacology & Pharmacy

Chemistry, Medicinal

WOS:000934155100001

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

CHEMISTRY

2-s2.0-85146905573

Scopus

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

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.

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.

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).