Chemical Targeting of Prolyl-tRNA Synthetase Stalls Ovarian Development and Kills Malaria Vectors.

Abstract

Along with rising resistance to antimalarials, the emergence of insecticide resistance in Anopheles mosquito species remains a serious concern. Here, we reveal 2 potent compounds that show larvicidal and endectocidal activity against malaria vectors Anopheles culicifacies and Anopheles stephensi. We investigated the larvicidal activity of 2 inhibitors against III instar larvae of A culicifacies. The survival and fertility of adult female A stephensi mosquitoes were also assessed with inhibitors. Additionally, we purified recombinant prolyl-tRNA synthetase of A culicifacies and performed enzyme-based assays and structural studies with the 2 inhibitors. Our study reveals that the A culicifacies prolyl-tRNA synthetase (AcProRS) is potently inhibited by halofuginone (HFG) and an adenosine triphosphate mimetic (L95). The evaluation of larvicidal activity of HFG against A culicifacies III instar larvae showed a dose-dependent increase in mortality. In adult female A stephensi mosquitoes, ingestion of HFG via artificial blood feeding resulted in impaired ovary development, reduced egg laying, and decreased overall survival. The potent enzymatic inhibition of AcProRS thus likely drives the killing of larvae. The cocrystal structure of AcProRS with inhibitors provides a structural basis for improving their potency as future larvicides. Our data suggest the potential for repositioning HFG and pyrrolidine-based adenosine triphosphate mimetic (L95) as larvicides. Targeting the vector-encoded aminoacyl-tRNA synthetases provides a new focus for developing effective agents that can control multiple mosquito-borne infectious diseases such as malaria and dengue.