Molecular Insights into the Potential Insecticidal Interaction of β-Dihydroagarofuran Derivatives with the H Subunit of V-ATPase.

Jielu Wei,Wenjun Wu,Jiwen Zhang,Lulu Liu,Ximei Zhao,Xin Xi,Ding Li

doi:10.3390/molecules22101701

Jielu Wei, Wenjun Wu + Show 5 more

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https://doi.org/10.3390/molecules22101701

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Abstract

Celangulin V (CV), one of dihydroagarofuran sesquiterpene polyesters isolated from Chinese bittersweet (Celastrus angulatus Maxim), is famous natural botanical insecticide. Decades of research suggests that is displays excellent insecticidal activity against some insects, such as Mythimna separata Walker. Recently, it has been validated that the H subunit of V-ATPase is one of the target proteins of the insecticidal dihydroagarofuran sesquiterpene polyesters. As a continuation of the development of new pesticides from these natural products, a series of β-dihydroagarofuran derivatives have been designed and synthesized. The compound JW-3, an insecticidal derivative of CV with a p-fluorobenzyl group, exhibits higher insecticidal activity than CV. In this study, the potential inhibitory effect aused by the interaction of JW-3 with the H subunit of V-ATPase c was verified by confirmatory experiments at the molecular level. Both spectroscopic techniques and isothermal titration calorimetry measurements showed the binding of JW-3 to the subunit H of V-ATPase was specific and spontaneous. In addition, the possible mechanism of action of the compound was discussed. Docking results indicated compound JW-3 could bind well in ‘the interdomain cleft’ of the V-ATPase subunit H by the hydrogen bonding and make conformation of the ligand–protein complex become more stable. All results are the further validations of the hypothesis, that the target protein of insecticidal dihydroagarofuran sesquiterpene polyesters and their β-dihydroagarofuran derivatives is the subunit H of V-ATPase. The results also provide new ideas for developing pesticides acting on V-ATPase of insects.

Highlights

Chinese bittersweet (Celastrus angulatus Maxim), which belongs to the family Celastraceae, has long been known for its medicinal and insecticidal properties, and lots of dihydroagarofuran sesquiterpene polyol esters extracted from this plant display excellent insecticidal activity [1,2,3,4,5,6,7]
Transmission electron microscopy (TEM) analysis show that celangulin V (CV) could induce time-dependent cytotoxicity in the midgut epithelial cells of Mythimna separata Walker larvae, such as visible vacuolization of cytoplasm, serious disruption of microvilli, fragmentation of RER
As a continuation of the development of new pesticides from these natural products, we have previously reported the design and synthesis of a series of β-dihydroagarofuran derivatives, which gave a good number of hit compounds through screening against the larvae of Mythimna separata Walker [9,10]

Summary

Introduction

Chinese bittersweet (Celastrus angulatus Maxim), which belongs to the family Celastraceae, has long been known for its medicinal and insecticidal properties, and lots of dihydroagarofuran sesquiterpene polyol esters extracted from this plant display excellent insecticidal activity [1,2,3,4,5,6,7]. These insecticidal compounds mainly affect the digestive system of pests, which after oral administration present a series of symptoms, such as excitement, twitching, emesis, and loss of body fluid [8]. Compound JW-3, an insecticidal derivative of CV with a p-fluorobenzyl group, could be used as a fluorescent probe for measurement of the interaction of β-dihydroagarofuran derivatives with their target biomacromolecule

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