biostudies-literature00440Correy GJGerman-Israeli Foundation for Scientific Research and DevelopmentIsrael Science FoundationAustralian Science and Industry Endowment FundAustralian Research Council21012-21021https://www.ebi.ac.uk/biostudies/studies/S-EPMC6800356biostudies-literatureUnknown116(42)Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest <i>Lucilia cuprina</i> as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill <i>L. cuprina</i> by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (<i>Myzus persicae</i>). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.Proceedings of the National Academy of Sciences of the United States of AmericaOvercoming insecticide resistance through computational inhibitor design.PMC68003561097/16I-2483-302.5/2017FT140101059PF14-099Mabbitt PDJames PJLondon NCorrey GJCalaora VCarvalho SKotze ACJackson CJZaidman DHarmelin A44falseOvercoming insecticide resistance through computational inhibitor design.Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest <i>Lucilia cuprina</i> as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill <i>L. cuprina</i> by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (<i>Myzus persicae</i>). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.2019-01-01T00:00:00Z2019 Oct2024-02-15T19:03:14.299Z2020-11-08T09:06:53ZS-EPMC68003563157574310.1073/pnas.1909130116