Dual-Specificity Inhibitor Targets Enzymes of the Trehalose Biosynthesis Pathway
Yitong Chen, Liu Tang, Zhiyang Jiang, Shanshan Wang, Linlu Qi, Xiaolin Tian, Haiteng Deng, Zhiwei Kong, Wenqiang Gao, Xiaokang Zhang, Saijie Li, Meiqing Chen, Xin Zhang, Hongxia Duan, Jun Yang, You‐Liang Peng, Dongli Wang, Junfeng Liu
Abstract
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.