Dual-Specificity Inhibitor Targets Enzymes of the Trehalose Biosynthesis Pathway

  • J Agric Food Chem. 2024 Jan 10;72(1):209-218. doi: 10.1021/acs.jafc.3c06946.
Yitong Chen  1 ,  Liu Tang  1 ,  Zhiyang Jiang  2 ,  Shanshan Wang  1 ,  Linlu Qi  1 ,  Xiaolin Tian  3 ,  Haiteng Deng  3 ,  Zhiwei Kong  1 ,  Wenqiang Gao  1 ,  Xiaokang Zhang  1 ,  Saijie Li  1 ,  Meiqing Chen  1 ,  Xin Zhang  1 ,  Hongxia Duan  2 ,  Jun Yang  1 ,  You-Liang Peng  1 ,  Dongli Wang  1 ,  Junfeng Liu  4
Affiliations
  • 1. Ministry of Agriculture Key Laboratory for Crop Pest Monitoring and Green Control, College of Plant Protection, China Agricultural University, Beijing 100193, China.
  • 2. Innovation Center of Pesticide Research, Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, China.
  • 3. MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4. Ministry of Agriculture Key Laboratory for Crop Pest Monitoring and Green Control, State Key Laboratory of Maize Bio-breeding, Joint International Research Laboratory of Crop Molecular Breeding, China Agricultural University, Beijing 100193, China.
PMID: 38128269 DOI: 10.1021/acs.jafc.3c06946
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.

Keywords
Magnaporthe oryzae; dual-specificity; inhibitor; trehalose biosynthesis.
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