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

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

  • Eur J Med Chem. 2023 Jan 10;249:115113. doi: 10.1016/j.ejmech.2023.115113.
Qifan Zhou 1,  Yinzhu Luo 2,  Yujun Zhu 2,  Qishu Chen 1,  Jingfei Qiu 1,  Feng Cong 3,  Yingjun Li 4,  Xumu Zhang 5
Affiliations

Affiliations

  • 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 Guangdong Province Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong, 510663, China. Electronic address: [email protected].
  • 4 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; State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China. Electronic address: [email protected].
  • 5 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. Electronic address: [email protected].
PMID: 36706621 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.

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