Professor Huang Jia's research group from the College of Agriculture published a paper in Science Advances to reveal new targets for insecticides

Chemical pesticides are widely used to control agricultural pests and vector insects and are indispensable and important tools
for maintaining food security and human health.
Insecticides that currently account for more than 80 per cent of the market act on the nervous system of insects, but these hundreds of nerve agents converge on eight known molecular targets, the most recent In 30 years, only a new target, the TRPV ion channel, has been discovered.

On November 24, Huang Jia's research group of Zhejiang University published a report entitled "An insecticide target in" in Science Advances Mechanoreceptor Neurons", by revealing the mechanism of action of the insecticide flufenamide, discovered the 9th molecular target in the insect nervous system - nicotinamide enzyme.

Flufenamide, first disclosed in a patent in 1994 and marketed in 2003, has a very good control effect against stingy mouthparts pests such as aphids, and is safe
against pollinating insects such as bees and parasitic bees and natural enemies.
Because of its unique mechanism of action, it causes behavioral disorders by interfering with the insect-specific proprioceptive chordotonal organ, the Insecticide Resistance Action Committee IRAC) early classified both flufenfenamide and pyraphenone, another insecticide with a similar mechanism of action, into group 9, i.
e.
, insecticides
belonging to the class of string regulators.
In 2015, a joint team from BASF and the University of Göttingen discovered that pyrafendone is an agonist of T RPV ion channels on the strings, and flufenamide was subsequently assigned to the new group 29 by the I RAC.
That is
, a string regulator whose target site is unknown.

Figure 1: Schematic diagram of the mechanism of action of flufenamide

Through a series of experiments such as behavioral genetics, enzyme kinetics, and comparative pharmacology in Drosophila, the authors found that nicotinamide is specifically expressed in the chordal neuron of Drosophila, and the metabolite T FNA-AM of flufenamide in worms leads to the accumulation of the substrate nicotinamide by inhibiting nicotinase activity, thereby overactivating T RPV ion channels produce symptoms of toxicity (Figure 1).

The introduction of a point mutation that reduces affinity for T FNA-AM at the catalytic site of nicotinase by C RISPR-Cas9 genome editing technology will lead to mutant fruit flies developing high resistance to flufenfenamide with gravity-sensing defects
.
In vitro recombinantly expressed nicotinamide enzymes of aphids and whiteflies were more sensitive to T FNA-AM, while bees produced a higher resistance nicotinamide homologous gene due to gene replication, which may be the main reason for the high virulence selectivity of flufenacamide for
different species.
Nicotinases are widespread in both nematodes and pathogenic bacteria and have important physiological functions, while the absence of a gene encoding nicotinase in the vertebrate genome means that TFNA-AM and potential nicotinamide inhibitors can also be developed for use in agriculture as nematicides and fungicides, Antiparasitic drugs and antibiotics can also be developed for medical use
.

Professor Huang Jia of the Institute of Insect Science of Zhejiang University is the corresponding author of the paper, postdoctoral fellow Qiao Xiaomu is the first author, graduate students Zhang Xiaoyu, Zhou Zhendong, Guo Lei, Wu Weiping, Ma Suhan, and associate researcher Zhang Xinzhong of the Tea Research Institute of the Chinese Academy of Agricultural Sciences and Professor Craig Montell of the University of California, Santa Barbara also participated in the study
。 Special thanks to Professor Kang Lijun and doctoral student Chen Du of Zhejiang University School of Medicine for their guidance
on nematode experimental technology.
The study was previously studied by Professor Huang Jia's group on tyramine receptors (Current Biology, 2016), serotonin receptors (eLife, 2016), octopamine receptors (eLife, 2021), acetylcholine receptors (Plos Genetics, 2022), another breakthrough achievement based on target research, and it is also the first time that Chinese scholars have discovered molecular targets for commercial pesticides and applied for related invention patents
.

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