Abstract
Aphids, among the most destructive insects to world agriculture, are mainly controlled by organophosphate insecticides that disable the catalytic serine residue of acetylcholinesterase (AChE). Because these agents also affect vertebrate AChEs, they are toxic to non-target species including humans and birds. We previously reported that a cysteine residue (Cys), found at the AChE active site in aphids and other insects but not mammals, might serve as a target for insect-selective pesticides. However, aphids have two different AChEs (termed AP and AO), and only AP-AChE carries the unique Cys. The absence of the active-site Cys in AO-AChE might raise concerns about the utility of targeting that residue. Herein we report the development of a methanethiosulfonate-containing small molecule that, at 6.0 µM, irreversibly inhibits 99% of all AChE activity extracted from the greenbug aphid (Schizaphis graminum) without any measurable inhibition of the human AChE. Reactivation studies using β-mercaptoethanol confirm that the irreversible inhibition resulted from the conjugation of the inhibitor to the unique Cys. These results suggest that AO-AChE does not contribute significantly to the overall AChE activity in aphids, thus offering new insight into the relative functional importance of the two insect AChEs. More importantly, by demonstrating that the Cys-targeting inhibitor can abolish AChE activity in aphids, we can conclude that the unique Cys may be a viable target for species-selective agents to control aphids without causing human toxicity and resistance problems.
Highlights
Aphids are among the world’s most destructive insect pests of grain crops, vegetables, ornamental plants, and fruit trees
Inspired by reference [21], we designed these inhibitors with (1) affinity for the greenbug AChE active site in order to build up their local concentration around Cys289 and (2) preferential reactivity to form an adduct with Cys289 or its equivalent, at the entrance to the active site, after binding near that locus (Figure 2)
Our multiple 10-ns-long molecular dynamics simulations of the greenbug AChE in complex with AMTS17 suggested that the 17-methylene-long inhibitor would tuck into the active site with (1) its thiol sulfur atom located 3.6-Aaway from the sulfur atom of Cys289 at the opening of the active site, while (2) its ammonium group engages in an ionic interaction with Glu201 as well as cation-pi interactions with Trp87, Tyr331, and Trp434 at the bottom of the active site (Figure 4a)
Summary
Aphids are among the world’s most destructive insect pests of grain crops, vegetables, ornamental plants, and fruit trees. Aphid control relies mainly on a small number of highly toxic anticholinesterases approved by the US Environmental Protection Agency (EPA); the threat to agriculture and environmental health is growing. This phenomenon is partly due to an unusual feature of aphid biology. During the aphid-growing season all aphids become female, and are able to produce offspring by maternal cloning in a process known as parthenogenesis This form of reproduction, with up to 18 asexual generations per growing season [3], allows aphids to develop resistance rapidly when few effective insecticides are applied repeatedly, as often happens in crops such as soybeans
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