2. Academic Validation
  3. Z-VAD(OMe)-FMK suppresses Seneca Valley Virus replication by targeting the active sites of the 3C protease

Z-VAD(OMe)-FMK suppresses Seneca Valley Virus replication by targeting the active sites of the 3C protease

  • Int J Biol Macromol. 2025 Mar 1;306(Pt 3):141587. doi: 10.1016/j.ijbiomac.2025.141587.
Lei Wu 1,  Ye Yuan 1,  Zhenchao Zhao 1,  Ya Yan 1,  Haiwei Wang 2,  Xin Li 3
Affiliations

Affiliations

  • 1 National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
  • 2 State Key Laboratory of Animal Disease Control, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China.
  • 3 National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Laboratory of Animal Epidemiology of the Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China. Electronic address: xinli2021@cau.edu.cn.
PMID: 40032110 DOI: 10.1016/j.ijbiomac.2025.141587
Abstract

Seneca Valley Virus (SVV) is a picornavirus that causes vesicular lesions in pigs, significantly affecting global swine farming. The SVV 3C protease is essential for processing the viral polyprotein and facilitates immune evasion by cleaving or degrading multiple innate immune proteins. In this study, we identified three Caspase inhibitors, including Z-VAD(OMe)-FMK (Z-VAD), Z-FA-FMK (Z-FA), and Z-VDVAD-FMK (Z-VDVAD), which significantly inhibit the cleavage activity of SVV 3C protease using a recombinant protein system. Comparative analysis revealed that Z-VAD exhibited the most potent inhibitory effect in a Cell Transfection system. Further investigations confirmed that Z-VAD, Z-FA, and Z-VDVAD bound directly to the 3C protein. Molecular docking analysis showed that Z-VAD interacted with key enzymatic site residues His48 and Cys160 of the 3C protease, while Z-VDVAD and Z-FA interacted only with residue Cys160. Infection experiments demonstrated that Z-VAD significantly suppressed the replication by targeting 3C protease. Furthermore, Z-VAD significantly suppressed the replication of Enterovirus A71 (EV-A71) and encephalomyocarditis virus (EMCV). Our findings provide a comprehensive understanding of SVV 3C Protease Inhibitors and their mechanisms of action, offering valuable insights for the development of strategies to control SVV and Other picornaviruses.

Keywords

3C protease; Inhibitor; Seneca Valley Virus; Z-VAD(OMe)-FMK.

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