title: An insecticide resistance-breaking mosquitocide targeting inward rectifier potassium channels in vectors of Zika virus and malaria.
abstract: Insecticide resistance is a growing threat to mosquito control programs around the world, thus creating the need to discover novel target sites and target-specific compounds for insecticide development. Emerging evidence suggests that mosquito inward rectifier potassium (Kir) channels represent viable molecular targets for developing insecticides with new mechanisms of action. Here we describe the discovery and characterization of VU041, a submicromolar-affinity inhibitor of Anopheles (An.) gambiae and Aedes (Ae.) aegypti Kir1 channels that incapacitates adult female mosquitoes from representative insecticide-susceptible and -resistant strains of An. gambiae (G3 and Akron, respectively) and Ae. aegypti (Liverpool and Puerto Rico, respectively) following topical application. VU041 is selective for mosquito Kir channels over several mammalian orthologs, with the exception of Kir2.1, and is not lethal to honey bees. Medicinal chemistry was used to develop an analog, termed VU730, which retains activity toward mosquito Kir1 but is not active against Kir2.1 or other mammalian Kir channels. Thus, VU041 and VU730 are promising chemical scaffolds for developing new classes of insecticides to combat insecticide-resistant mosquitoes and the transmission of mosquito-borne diseases, such as Zika virus, without harmful effects on humans and beneficial insects.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Entomology, Louisiana State University Agricultural Center, Baton Rouge, LA, 70803, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Swale
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Engers
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Bollinger
authors.affiliation: Department of Entomology and Nematology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Gross
authors.affiliation: Department of Entomology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.
authors.forename: Edna Alfaro
authors.initials: EA
authors.lastname: Inocente
authors.affiliation: Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Days
authors.affiliation: Department of Entomology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.
authors.forename: Fariba
authors.initials: F
authors.lastname: Kanga
authors.affiliation: Department of Entomology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.
authors.forename: Reed M
authors.initials: RM
authors.lastname: Johnson
authors.affiliation: Department of Entomology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Entomology and Nematology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bloomquist
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.affiliation: Department of Entomology, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, OH 44691, USA.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Piermarini
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.|Vanderbilt Institute of Chemical Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Institute for Global Health, Vanderbilt University, Nashville, TN 37203, USA.
authors.forename: Jerod S
authors.initials: JS
authors.lastname: Denton
mesh_terms: D000330:Aedes / Q000187:drug effects*; D000818:Animals; D000852:Anopheles / Q000187:drug effects*; D001516:Bees / Q000187:drug effects; D007305:Insecticide Resistance / Q000187:drug effects*; D007306:Insecticides / Q000494:pharmacology*; D000072138:Mosquito Vectors / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors*
chemical_list: D007306:Insecticides; D024661:Potassium Channels, Inwardly Rectifying