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.