Structural basis for substrate recognition and inhibition of thioredoxin glutathione reductase from Schistosoma japonicum: Implications for antiparasitic development

  • PLoS Pathog. 2026 Apr 24;22(4):e1014125. doi: 10.1371/journal.ppat.1014125.
Songqing Wang  1 ,  Wenbin Hong  2 ,  Shukun Zhong  3  4 ,  Zhijian Liang  1 ,  Tianyichen Xiao  1 ,  Chuchu Zhang  1 ,  Xianshu Liu  3  4 ,  Ziyi Dai  3  4 ,  Yunlong Li  1 ,  Siqi Wu  1 ,  Qixu Cai  5 ,  Caiming Wu  1 ,  Yuxuan Huang  2 ,  Peicheng Hong  1 ,  Haixia Ren  1 ,  Shaowei Li  6  7 ,  Tianwei Lin  1 ,  Xueqin Chen  2 ,  Shuaiqin Huang  3  4
Affiliations
  • 1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
  • 2. Xiamen Key Laboratory of Clinical Efficacy and Evidence Studies of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 3. Department of Medical Parasitology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
  • 4. Key Laboratory of Hunan Province for Schistosomiasis Immunity and Transmission Control, Yueyang, Hunan, China.
  • 5. State Key Laboratory of Vaccines for Infectious Diseases, School of Public Health, Xiamen University, Xiamen, Fujian, China.
  • 6. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, Fujian, China.
  • 7. State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, Fujian, China.
PMID: 42030356 DOI: 10.1371/journal.ppat.1014125
Abstract

Praziquantel (PZQ) is currently the only agent for treating schistosomiasis, but it is plagued by suboptimal efficacy to juvenile parasites, looming drug resistance, and inability to prevent reinfection. Thioredoxin glutathione reductase (TGR) is regarded as a promising therapeutic target due to its essential role in maintaining Schistosome redox homeostasis. Herein, the crystal structures of Schistosoma japonicum TGR (SjTGR) in multiple redox states and in complex with NADPH, GSH, and the anti-helminthic agent Auranofin were elucidated. Structural analyses identified the hook-shaped conformation at the C-terminal redox center, which DTNB assays further confirmed enhances electron transfer efficiency. Structural and ITC data indicated that R317 was critical for NADPH binding via hydrogen-bond interactions. The analysis also indicated that the structure basis of Auranofin's potency was its tripartite interaction at the redox-active sites. In addition, we investigated the substrate specificity of SjTrx1i and SjTRP14, downstream proteins regulated by SjTGR, and elucidated the structural basis for this specificity by determining their oxidized/reduced structures. Furthermore, in vivo RNAi indicated knockdown of SjTGR or SjTRP14 blocked the survival and oviposition of schistosomes, thus ameliorating egg-induced granulomatous pathology in mice. This work provided a framework for knowledge-based design of novel anti-schistosomals targeting parasite-specific redox vulnerabilities.

Products