2. Academic Validation
  3. Structure-based discovery of dual-target inhibitors of the helicase from bagaza virus

Structure-based discovery of dual-target inhibitors of the helicase from bagaza virus

  • Int J Biol Macromol. 2025 Mar:294:139536. doi: 10.1016/j.ijbiomac.2025.139536.
Rong Zhao 1,  Wen Shu 1,  Wen-Shu Hu 1,  Chen Chen 2,  Jun-Ya Ning 1,  Jing Luo 3,  Shang-Peng Bai 4,  Ji-Min Cao 5,  Xin Zhou 6,  De-Ping Wang 7
Affiliations

Affiliations

  • 1 Department of Cardiology, the First hospital of Shanxi Medical University, and MOE Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China.
  • 2 Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.
  • 3 Department of Rheumatology, the Second Hospital of Shanxi Medical University, Taiyuan, China.
  • 4 Shanxi Cancer Hospital, Taiyuan, China.
  • 5 Department of Cardiology, the First hospital of Shanxi Medical University, and MOE Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China. Electronic address: caojimin@sxmu.edu.cn.
  • 6 Department of Cardiology, the First hospital of Shanxi Medical University, and MOE Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China. Electronic address: xzhou@sxmu.edu.cn.
  • 7 Department of Cardiology, the First hospital of Shanxi Medical University, and MOE Key Laboratory of Cellular Physiology at Shanxi Medical University, Taiyuan, China. Electronic address: wangdeping@sxmu.edu.cn.
PMID: 39765299 DOI: 10.1016/j.ijbiomac.2025.139536
Abstract

Bagaza virus (BAGV) is a mosquito-borne Flavivirus and has caused significant avian death in many regions, and also garnered recognition as a significant human pathogen causing diseases like encephalitis. The genome of BAGV encodes ten proteins including three structural proteins and seven nonstructural proteins. The C-terminus of the BAGV NS3 helicase serves as a helicase during BAGV replication, aiding in ATP hydrolysis and unwinding of double-stranded RNA. Here we determined the crystal structure of BAGV helicase and revealed the NTP and RNA binding pockets in the helicase which may be used for exploiting Antiviral therapeutics. Using structure-based virtual screening, we discovered 20 compounds targeting both NTP and RNA binding pockets of the helicase. Molecular docking, mutation analysis, isothermal calorimetry (ITC) and the ATPase activity assay demonstrated that epigallocatechin-3-gallate (EGCG), and Other top three screened compounds (Quercitrin, Citicoline sodium, Isochlorogenic acid C), showed binding affinities for both the NTP binding site and the RNA binding site of BAGV helicase, and inhibited the ATPase activity of the helicase. Taken together, our discovery of dual-target inhibitors provides a viable strategy for advancing innovative therapies against BAGV, as well as Other flaviviruses.

Keywords

Bagaza virus; Crystal structure; NS3 helicase.

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