tetano
Editor, Senior Moderator
Eur J Med Chem
. 2023 Jan 10;249:115113.
doi: 10.1016/j.ejmech.2023.115113. Online ahead of print.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses
Qifan Zhou[SUP] 1 [/SUP], Yinzhu Luo[SUP] 2 [/SUP], Yujun Zhu[SUP] 2 [/SUP], Qishu Chen[SUP] 1 [/SUP], Jingfei Qiu[SUP] 1 [/SUP], Feng Cong[SUP] 3 [/SUP], Yingjun Li[SUP] 4 [/SUP], Xumu Zhang[SUP] 5 [/SUP]
Affiliations
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: Coronavirus; Ibuprofen; NSAIDs; Nucleotide; Oral antiviral agent; RNA dependent RNA polymerase.
. 2023 Jan 10;249:115113.
doi: 10.1016/j.ejmech.2023.115113. Online ahead of print.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses
Qifan Zhou[SUP] 1 [/SUP], Yinzhu Luo[SUP] 2 [/SUP], Yujun Zhu[SUP] 2 [/SUP], Qishu Chen[SUP] 1 [/SUP], Jingfei Qiu[SUP] 1 [/SUP], Feng Cong[SUP] 3 [/SUP], Yingjun Li[SUP] 4 [/SUP], Xumu Zhang[SUP] 5 [/SUP]
Affiliations
- PMID: 36706621
- PMCID: PMC9830933
- DOI: 10.1016/j.ejmech.2023.115113
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: Coronavirus; Ibuprofen; NSAIDs; Nucleotide; Oral antiviral agent; RNA dependent RNA polymerase.