Discovery of Selective Inhibitors Targeting Acetylcholinesterase 1 from Disease-Transmitting Mosquitoes

Abstract

Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.

Select β- and γ-branched 1-alkylpyrazol-4-yl methylcarbamates exhibit high selectivity for inhibition of Anopheles gambiae versus human acetylcholinesterase

“…In addition, 13 and analogs were demonstrated to be toxic to susceptible adult An. gambi ae [16, 17]. However, inhibitory potency of 13 against G119S Ag AChE was poor [17].…”

An Unusual Dimeric Inhibitor of Acetylcholinesterase: Cooperative Binding of Crystal Violet

“…We have previously reported the in vitro screening campaigns of a chemically diverse library consisting of 17,500 drug-like compounds. The screens were performed using AChEs derived from Homo sapiens ( h AChE), Anopheles gambiae ( Ag AChE), and Aedis aegypti ( Aa AChE), and collectively led to the discovery of 425 unique hits that significantly reduced the enzymatic activity at a concentration of 50 µM [ 10 , 11 ]. Subsequent hit confirmation resulted in the determination of the half maximal inhibitory concentration values (IC 50 ) and Hill coefficients ( n H ) for 106 compounds.…”

Anopheles metabolic proteins in malaria transmission, prevention and control: a review

“…Some studies have identified inhibitors that have greater selectivity for AgAChE than hAChE. An example of this was reported in a study in which differential high throughput screening (HTS) of several compounds for selective inhibition of AgAChE was carried out [47]. One of the selective inhibitors identified in their study was a phenoxyacetamide-based inhibitor that was 100-times more selective for AgAChE than for hAChE.…”