Discovery of Species-selective and Resistance-breaking Anticholinesterase Insecticides for the Malaria Mosquito

Abstract

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.

Structure of the G119S Mutant Acetylcholinesterase of the Malaria Vector Anopheles gambiae Reveals Basis of Insecticide Resistance

“…Individual AChE inhibitors can exhibit significantly different potencies towards Ag AChE and hAChE (Carlier et al, 2008; Hartsel et al, 2012; Carlier et al 2017). This is not surprising as differences in gorge structure are known to affect binding of ligands in more closely related AChEs (Cheung et al, 2012).…”

“…The challenge remains therefore, to develop inhibitors that are highly selective for both WT and G280S Ag AChE vs hAChE (Carlier et al, 2017). In this regard, the positioning of C447 in the acyl loop at the surface of the gorge is noteworthy, and matches previous predictions (Pang, 2006).…”

Compensatory mechanisms in resistant Anopheles gambiae AcerKis and KdrKis neurons modulate insecticide-based mosquito control

“…These compensatory mechanisms appear to be the consequences of the point mutation in the voltage-gated sodium channels 5 , 9 , 24 and AChE1 genes 25 , 26 , 45 characterized in KdrKis and AcerKis Anopheles gambiae , respectively. In the AcerKis strain, previous findings and this study reveal that AChE activity is strongly reduced.…”

“…To the best of our knowledge, in this study we investigate in mosquitoes the neuronal compensatory mechanisms following the development of resistance-associated point mutations in the voltage-gated sodium channels 5 , 24 and AChE1 25 , 26 genes characterized in two strains of Anopheles gambiae resistant to two distinct classes of insecticides, the pyrethroid/DDT-resistant strain, named KdrKis ( kdr R , L1014F) and the organophosphate/carbamate-resistant strain, named AcerKis ( ace-1 R , G119S). We use multidisciplinary approaches adapted to isolated Anopheles gambiae neurons 27 to characterize changes in the expression and pharmacological profile of neuronal nicotinic acetylcholine receptors (nAChRs) following the mutations G119S in AcerKis strain and L1014F in KdrKis strain compared to the susceptible laboratory reference Anopheles gambiae Kis strain.…”

Characterization of the Fifth Putative Acetylcholinesterase in the Wolf Spider, Pardosa pseudoannulata

“…As a dominating neurotransmitter hydrolase, acetylcholinesterases (AChEs) extensively exist in invertebrate and vertebrate nervous systems, and effectively hydrolyse acetylcholine to maintain the normal nerve conduction. The importance of AChEs makes it a research hotspot in human medical treatments and agricultural pest management [ 1 , 2 , 3 , 4 , 5 ]. Besides the classical synaptic hydrolytic function, a variety of AChEs non-cholinergic functions have been found [ 6 , 7 , 8 ].…”