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Publication Abstract from PubMed

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 non-covalent 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. Non-covalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points towards insecticides and are complementarity to existing and new covalent inhibitors.

Discovery of selective inhibitors targeting acetylcholinesterase 1 from disease-transmitting mosquitoes.,Engdahl C, Knutsson S, Ekstrom FJ, Linusson A J Med Chem. 2016 Sep 6. PMID:27598521^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.