Dual-Specificity Inhibitor Targets Enzymes of the Trehalose Biosynthesis Pathway

• Published in: Journal of agricultural and food chemistry Vol. 72; no. 1; pp. 209 - 218
• Main Authors: Chen, Yitong, Tang, Liu, Jiang, Zhiyang, Wang, Shanshan, Qi, Linlu, Tian, Xiaolin, Deng, Haiteng, Kong, Zhiwei, Gao, Wenqiang, Zhang, Xiaokang, Li, Saijie, Chen, Meiqing, Zhang, Xin, Duan, Hongxia, Yang, Jun, Peng, You-Liang, Wang, Dongli, Liu, Junfeng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.01.2024
• Subjects: Agricultural and Environmental Chemistry; Animals; Carbohydrate Metabolism; Fungicides, Industrial - pharmacology; Glucosyltransferases - chemistry; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; Trehalose - metabolism; Magnaporthe oryzae; dual-specificity; trehalose biosynthesis; inhibitor
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.3c06946

To reduce the risk of resistance development, a novel fungicide with dual specificity is demanded. Trehalose is absent in animals, and its synthases, trehalose-6-phosphate synthase (TPS) and trehalose-6-phosphate phosphatase (TPP), are safe fungicide targets. Here, we report the discovery of a dual-specificity inhibitor of MoTps1 (Magnaporthe oryzae Tps1, TPS) and MoTps2 (M. oryzae Tps2, TPP). The inhibitor, named A1-4, was obtained from a virtual screening and subsequent surface plasmon resonance screening. In in vitro assays, A1-4 interacts with MoTps1 and MoTps2-TPP (MoTps2 TPP domain) and inhibits their enzyme activities. In biological activity assays, A1-4 not only inhibits the virulence of M. oryzae on host but also causes aggregation of conidia cytosol, which is a characteristic phenotype of MoTps2. Furthermore, hydrogen/deuterium exchange mass spectrometry assays support the notion that A1-4 binds to the substrate pockets of TPS and TPP. Collectively, A1-4 is a promising hit compound for the development of safe fungicide with dual-target specificity.