Design, Synthesis, and Biological Assessment of Potent Covalent Inhibitors of Insect UDP- N-acetylglucosamine Pyrophosphorylase

  • J Agric Food Chem. 2026 May 20;74(19):14834-14842. doi: 10.1021/acs.jafc.5c14427.
Xingyue Zhou  1 ,  Qiong Lu  2 ,  Yanjun Zhang  1 ,  Yin Ai  1 ,  Jianyang Li  1 ,  Tian Liu  2 ,  Jianjun Zhang  1
Affiliations
  • 1. Department of Applied Chemistry, China Agricultural University, Beijing100193, China.
  • 2. MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian116024, China.
PMID: 42093454 DOI: 10.1021/acs.jafc.5c14427
Abstract

Insect UDP-N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the formation of UDP-N-acetylglucosamine, which is a precursor of chitin synthesis. This makes UAP a promising molecular target for developing green pesticides. Inspired by a Cys334-covalent strategy, a series of maleimide derivatives against insect UAP were designed and synthesized. Enzyme activity assays revealed that all tested compounds exhibited potent inhibitory activity. Thereinto, the respective IC50 were 150 ± 10, 124 ± 26, and 108 ± 20 nM for compounds A5, A10, and A15 against SfUAP. Furthermore, time-dependent inhibition assays revealed that the IC50 of A15 decreased to 13.0 nM upon extending the incubation time to 60 min, supporting a time-dependent inhibitory profile; covalent docking simulations further corroborated a covalent binding mechanism. Bioassays demonstrated that A15 significantly inhibited the growth and development of Plutella xylostella, Spodoptera frugiperda, and Spodoptera litura. Overall, this study provides a template for designing more UAP inhibitors with covalent characteristics.

Keywords
MD simulations; UDP-N-acetylglucosamine pyrophosphorylase; covalent docking; covalent inhibitors; insecticides.
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