Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito.
Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets only employ pyrethroids, insecticides that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess low mammalian toxicity. In this review, we will describe efforts to develop highly species-specific and resistance-breaking inhibitors of An. gambiae acetylcholinesterase (AgAChE). These efforts have been greatly aided by advances in knowledge of the structure of the enzyme, and two major inhibitor design strategies have been explored. Since AgAChE possesses an unpaired Cys residue not present in mammalian AChE, a logical strategy to achieve selective inhibition involves design of compounds that could ligate that Cys. A second strategy involves the design of new molecules to target the catalytic serine of the enzyme. Here the challenge is not only to achieve high inhibition selectivity vs human AChE, but also to demonstrate toxicity to An. gambiae that carry the G119S resistance mutation of AgAChE. The advances made and challenges remaining will be presented. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity".
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061. United States.
Paul R
PR
Carlier
Department of Entomology and Nematology and Emerging Pathogens Institute, University of Florida, 2055 Mowry Road, P.O. Box 100009, Gainesville, FL 32610-00009. United States.
Jeffrey R
JR
Bloomquist
Molsoft LLC, 11199 Sorrento Valley Road, San Diego, CA 92121. United States.
Max
M
Totrov
Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061. United States.
Jianyong
J
Li
D000110:Acetylcholinesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000852:Anopheles / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D055808:Drug Discovery; D004351:Drug Resistance / Q000187:drug effects; D006801:Humans; D007303:Insect Vectors / Q000187:drug effects; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D007659:Ketones / Q000737:chemistry / Q000378:metabolism; D013045:Species Specificity
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D007659:Ketones; D000110:Acetylcholinesterase
Acetylcholinesterase; carbamates; cysteine; difluoromethyl
ketones.; sulfhydryl reagents; trifluoromethyl ketones