Dopamine receptor antagonists as new mode-of-action insecticide leads for control of Aedes and Culex mosquito vectors

PLoS Neglected Tropical Diseases
Andrew B NussCatherine A Hill

Abstract

New mode-of-action insecticides are sought to provide continued control of pesticide resistant arthropod vectors of neglected tropical diseases (NTDs). We previously identified antagonists of the AaDOP2 D1-like dopamine receptor (DAR) from the yellow fever mosquito, Aedes aegypti, with toxicity to Ae. aegypti larvae as leads for novel insecticides. To extend DAR-based insecticide discovery, we evaluated the molecular and pharmacological characteristics of an orthologous DAR target, CqDOP2, from Culex quinquefasciatus, the vector of lymphatic filariasis and West Nile virus. CqDOP2 has 94.7% amino acid identity to AaDOP2 and 28.3% identity to the human D1-like DAR, hD1. CqDOP2 and AaDOP2 exhibited similar pharmacological responses to biogenic amines and DAR antagonists in cell-based assays. The antagonists amitriptyline, amperozide, asenapine, chlorpromazine and doxepin were between 35 to 227-fold more selective at inhibiting the response of CqDOP2 and AaDOP2 in comparison to hD1. Antagonists were toxic to both C. quinquefasciatus and Ae. aegypti larvae, with LC50 values ranging from 41 to 208 μM 72 h post-exposure. Orthologous DOP2 receptors identified from the African malaria mosquito, Anopheles gambiae, the sand fly, Phlebotom...Continue Reading

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Citations

Feb 10, 2016·Nature Communications·Monika Gulia-NussCatherine A Hill
Mar 18, 2017·Insect Biochemistry and Molecular Biology·Gang XuJia Huang
Jan 19, 2021·Journal of Insect Physiology·Alexander Soohoo-HuiDaniel R Swale
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Nannan LiuShikai Liu
Jun 25, 2021·Infection, Genetics and Evolution : Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases·Muhammad FiazJosé Eduardo Serrão
Oct 20, 2018·Journal of Medicinal Chemistry·Sofie KnutssonAnna Linusson
Jun 1, 2018·Chemical Research in Toxicology·Monika SchmidtKamil Musilek

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Datasets Mentioned

BETA
KM262648
ABKP02020596
AJVK01013961

Methods Mentioned

BETA
electrophoresis
glycosylation

Software Mentioned

Aa DOP2
GraphPad
Basic Local Alignment Search Tool ( tBLASTn
ClustalW
Artemis
PIDP
GraphPad Prism
tBLASTn
MEGA6

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