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Structural Genomics Approach to Discover Mammal-Safe Insecticides


The long-term goal is to develop conceptually-new insecticides with reduced resistance from insects and reduced toxicity toward non-target species.<P> The proposed objectives toward the goal are (1) development of 50 cysteine-reacting inhibitors that inhibit aphid acetylcholinesterases (aAChE) but not human acetylcholinesterase (hAChE), (2) identification of a subset of the 50 inhibitors that show no or lower toxicity to rats than current insecticides, and (3) identification of a subset of the cysteine-reacting and low-mammal-toxicity inhibitors that show high aphicidal efficacy. <P>The year-1 milestone is to deliver aAChE inhibitors with in vitro efficacy. The criterion for measuring completion of the milestone is that the new inhibitors show 100% and 0% inhibitions of aAChE and hAChE, respectively, at an inhibitor concentration of 500 nM. The year-2 milestone is to deliver aAChE inhibitors with in vivo efficacy. The criterion is that the new inhibitors have an LC90 of <50 ug/L for soybean aphid and an oral LD50 of >5000 mg/kg to rats.

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Non-Technical Summary: Current anticholinesterase insecticides chemically disable the catalytic serine residue of acetylcholinesterase (AChE) that occurs in all species with cholinergic nerves. These chemicals are therefore toxic to mammals, fish, birds, and arthropods. Recently, we discovered that a chemically reactive cysteine residue is present in the AChE active site of crop pests but absent in those of mammals, fish, and birds (PLoS ONE, 1: e58 2006), and we proved the concept that chemicals designed to react with the cysteine residue can cripple insect AChEs but not human AChE (PLoS ONE, 4: e4349 2009; 4:e6851, 2009). In this context, we propose to develop conceptually novel insecticides that react only with the insect-specific cysteine residue. The new insecticides will have reduced resistance from insects because a much longer time is needed for insects to develop resistance to cysteine-reacting chemicals than serine-reacting chemicals due to different locations of the cysteine and serine residues in AChE. The cysteine-targeting insecticides will also have reduced toxicity to non-target species because only insects have the reactive cysteine residue in AChE. Realization of this project can (1) improve economies in rural and agricultural communities by using new insecticides to effectively reduce crop damage, and (2) reduce the Nation's dependence on insecticides with a broad spectrum of toxicity. <P> Approach: We will employ computational and synthetic chemistry and pharmacology to design, synthesize and test the desired insect-specific AChE inhibitors for objective 1. We will use established methods in toxicology to identify insect-specific and "mammal-safe" AChE inhibitors for objective 2. We will perform in vivo assays using a rich collection of different aphids that are either susceptible or resistant to current insecticides for objective 3. The unique aspect of our approaches to the problems is an unusual combination of the cutting-edge technologies in chemistry, pharmacology, toxicology, and entomology. See detailed information in PLoS ONE 1: e58, 2006; 4:e4349, 2009; and 4:e6851, 2009.

Pang, Yuan-Ping
Mayo Clinic College of Medicine
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