Overcoming insecticide resistance through computational inhibitor design

Area of Science:

• Agricultural Science
• Biochemistry
• Toxicology

Background:

• Insecticide resistance, particularly to organophosphates (OPs), threatens global food security and public health.
• Carboxylesterases are key enzymes involved in OP resistance through sequestration or hydrolysis.
• Developing strategies to overcome insecticide resistance is crucial for sustainable agriculture and disease vector control.

Purpose of the Study:

• To identify and develop novel inhibitors of carboxylesterases to overcome OP resistance.
• To assess the efficacy and safety of these inhibitors in agricultural pest models.
• To explore the potential of these inhibitors to reduce overall insecticide usage.

Main Methods:

• Covalent virtual screening was employed to design boronic acid inhibitors.
• Inhibitors were tested against the carboxylesterase αE7 from *Lucilia cuprina* and its resistant mutant.
• Synergistic effects with OPs (diazinon, malathion, chlorpyrifos) were evaluated in pest models.
• Selectivity against human acetylcholinesterase and toxicity in human cells and mice were assessed.

Main Results:

• Nano-/picomolar boronic acid inhibitors of αE7 carboxylesterase were successfully developed.
• These inhibitors demonstrated high selectivity against human acetylcholinesterase and low toxicity.
• Inhibitors synergized with OPs, reducing required amounts by up to 16-fold and abolishing resistance in *L. cuprina*.
• Compounds potentiated chlorpyrifos efficacy against *Myzus persicae*.

Conclusions:

• Developed boronic acid inhibitors effectively overcome OP resistance by targeting carboxylesterases.
• These compounds offer a dual solution for insecticide resistance and reduced environmental impact of OPs.
• The findings pave the way for more sustainable pest and vector control strategies.